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Yenisel Cruz-Almeida,1–3 Maria Aguirre,1,4 Heather Sorenson,4,5 Patrick Tighe,1,6 Shannon M Wallet,4,5 Joseph L Riley III1,4 1Pain Research and Intervention Center of Excellence, 2Institute on Aging, 3Department of Aging and Geriatric Research, 4Department of Community Dentistry & Behavioral Science, 5Department of Oral Biology, 6Department of Anesthesiology, University of Florida, Gainesville, FL, USA Abstract: An important consideration in mechanistic research using biomarkers should include the use of saliva as an alternative to blood. The use of saliva would allow the study of susceptible populations such as older adults where venipuncture may not be feasible. Although saliva has been most commonly used to measure cortisol and tumor necrosis factor-α (TNFα), there is limited evidence that other cytokines found in saliva significantly change in response to laboratory-induced pain. Therefore, the aim of the current preliminary study was to characterize the time course, duration and magnitude of changes of commonly measured pro- (interleukin [IL]-6, IL-8) and anti-inflammatory (IL-10, IL-4) cytokines in saliva samples and to test for age-related differences in separate experimental painful and non-painful control sessions. In addition, we also tested whether venipuncture results in significant cytokine alterations similar to a painful stimulus in a non-painful, non-venipuncture control session. All cytokines were significantly induced by the cold pressor task compared to a warm control session (p < 0.001). Specifically, healthy older adults experienced greater salivary changes in all cytokines during the cold pressor session compared to younger adults in the non-painful sessions (p < 0.001). There were no significant differences between the venipuncture and non-venipuncture sessions across all cytokines (p > 0.05). Our findings support the use of saliva as a substitute for blood in both young and older healthy individuals to measure changes after experimental pain stimulation. In addition, venipuncture alone is not sufficient to induce IL-6, IL-8, IL-10 and IL-4. Future studies in the community are urgently needed to validate and further move translational mechanistic pain research to those populations most underrepresented in clinical research. Keywords: salivary markers, experimental pain, age, venipuncture

Abstract This report describes the characteristics and outcomes of 18 heavily pretreated patients with multiple myeloma (MM) who were subsequently treated with selinexor. This is a case series of 18 patients with MM who were treated with selinexor and dexamethasone (Sd) or selinexor, bortezomib, and dexamethasone (SVd) in 12 hospitals in the UK between 2019 and 2021. Eight patients received Sd and 10 patients received SVd. Patients received a median of five prior treatment lines, including immunomodulatory agents in 94% and proteasome inhibitors in 94%. Ten patients (55%) had triple‐class refractory disease. Six of the 12 evaluable patients achieved ≥partial response. The median progression‐free survival was 5.6 months, which was higher with SVd (5.7 months) than with Sd (2.1 months). The results support a treatment benefit of selinexor in heavily pretreated patients and support the notion that selinexor may overcome resistance to prior therapies, with no new safety concerns arising.

Abstract Background Poor memory for treatment is associated with poorer treatment adherence and poorer patient outcomes. The memory support intervention (MSI) was developed to improve patient memory for treatment with the goal of improving patient outcomes. The aim of this study protocol is to conduct a confirmatory efficacy trial to test whether a new, streamlined, and potent version of the MSI improves outcomes for midlife and older adults. This streamlined MSI is comprised of constructive memory supports that will be applied to a broader range of treatment content. The platform for this study is the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C). We will focus on midlife and older adults who are low income and experiencing mobility impairments. Methods Participants (N = 178) will be randomly allocated to TranS-C + MSI or TranS-C alone. Both intervention arms include eight 50-min weekly sessions. Assessments will be conducted at pre-treatment, post-treatment, 6-, and 12-month follow-up (6FU and 12FU). Aim 1 will compare the effects of TranS-C + MSI versus TranS-C alone on sleep and circadian functioning, daytime functioning, well-being, and patient memory. Aim 2 will test whether patient memory for treatment mediates the relationship between treatment condition and patient outcomes. Aim 3 will evaluate if previously reported poor treatment response subgroups will moderate the relationship between treatment condition and (a) patient memory for treatment and (b) treatment outcome. Exploratory analyses will compare treatment condition on (a) patient adherence, patient-rated treatment credibility, and patient utilization of treatment contents, and (b) provider-rated acceptability, appropriateness, and feasibility. Discussion This study has the potential to provide evidence for (a) the efficacy of a new simplified version of the MSI for maintaining health, well-being, and functioning, (b) the wider application of the MSI for midlife and older adults and to the treatment of sleep and circadian problems, and (c) the efficacy of the MSI for sub-groups who are likely to benefit from the intervention. Trial registration ClinicalTrials.gov NCT05986604. Registered on 2 August 2023.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease without meaningful therapeutic options beyond the first salvage therapy. Targeting PDAC metabolism through amino acid restriction has emerged as a promising new strategy, with asparaginases, enzymes that deplete plasma glutamine and asparagine, reaching clinical trials. In this study, we investigated the anti-PDAC activity of the asparaginase formulation Pegcrisantaspase (PegC) alone and in combination with standard-of-care chemotherapeutics. Methods Using mouse and human PDAC cell lines, we assessed the impact of PegC on cell proliferation, cell death, and cell cycle progression. We further characterized the in vitro effect of PegC on protein synthesis as well as the generation of reactive oxygen species and levels of glutathione, a major cellular antioxidant. Additional cell line studies examined the effect of the combination of PegC with standard-of-care chemotherapeutics. In vivo, the tolerability and efficacy of PegC, as well as the impact on plasma amino acid levels, was assessed using the C57BL/6-derived KPC syngeneic mouse model. Results Here we report that PegC demonstrated potent anti-proliferative activity in a panel of human and murine PDAC cell lines. This decrease in proliferation was accompanied by inhibited protein synthesis and decreased levels of glutathione. In vivo, PegC was tolerable and effectively reduced plasma levels of glutamine and asparagine, leading to a statistically significant inhibition of tumor growth in a syngeneic mouse model of PDAC. There was no observable in vitro or in vivo benefit to combining PegC with standard-of-care chemotherapeutics, including oxaliplatin, irinotecan, 5-fluorouracil, paclitaxel, and gemcitabine. Notably, PegC treatment increased tumor expression of asparagine and serine biosynthetic enzymes. Conclusions Taken together, our results demonstrate the potential therapeutic use of PegC in PDAC and highlight the importance of identifying candidates for combination regimens that could improve cytotoxicity and/or reduce the induction of resistance pathways.

Abstract Members of the family Trichomeriaceae, belonging to the Chaetothyriales order and the Ascomycota phylum, are known for their capability to inhabit hostile environments characterized by extreme temperatures, oligotrophic conditions, drought, or presence of toxic compounds. The genus Knufia encompasses many polyextremophilic species. In this report, the genomic and morphological features of the strain FJI-L2-BK-P2 presented, which was isolated from the Mars 2020 mission spacecraft assembly facility located at the Jet Propulsion Laboratory in Pasadena, California. The identification is based on sequence alignment for marker genes, multi-locus sequence analysis, and whole genome sequence phylogeny. The morphological features were studied using a diverse range of microscopic techniques (bright field, phase contrast, differential interference contrast and scanning electron microscopy). The phylogenetic marker genes of the strain FJI-L2-BK-P2 exhibited highest similarities with type strain of Knufia obscura (CBS 148926T) that was isolated from the gas tank of a car in Italy. To validate the species identity, whole genomes of both strains (FJI-L2-BK-P2 and CBS 148926T) were sequenced, annotated, and strain FJI-L2-BK-P2 was confirmed as K. obscura. The morphological analysis and description of the genomic characteristics of K. obscura FJI-L2-BK-P2 may contribute to refining the taxonomy of Knufia species. Key morphological features are reported in this K. obscura strain, resembling microsclerotia and chlamydospore-like propagules. These features known to be characteristic features in black fungi which could potentially facilitate their adaptation to harsh environments.

Paediatric patients often present with symptoms of respiratory illnesses in the weeks leading up to surgery. Current or recent illness can increase the risk of experiencing perioperative respiratory complications. Ideally, children with recent illnesses should be identified before coming to the hospital to determine the safest course of action. We recognised that our system lacked a standardised process for documenting preoperative respiratory illness during the preoperative phone call. The global aim of this quality improvement initiative was to decrease paediatric perioperative respiratory adverse events. The SMART Aim (Specific, Measurable, Achievable, Relevant and Time-bound) was to increase the percentage of patients with standardised documentation of preoperative respiratory illness from 0% to 90% by 1 March 2023. Implementation of a standardised preoperative illness questionnaire increased standardised illness documentation from 0% to 95%. Nurses quickly adopted this intervention and easily integrated it into their routine workflow. Clinical leaders elected to implement the intervention electronically across all three operating room (OR) locations (main OR, satellite location and procedure centre). Future implementation of additional standardised preoperative processes will be needed to improve the global aim of decreasing perioperative respiratory complications.

The degree to which artificial intelligence healthcare research is informed by data and stakeholders from community settings has not been previously described. As communities are the principal location of healthcare delivery, engaging them could represent an important opportunity to improve scientific quality. This scoping review systematically maps what is known and unknown about community-engaged artificial intelligence research and identifies opportunities to optimize the generalizability of these applications through involvement of community stakeholders and data throughout model development, validation, and implementation. Embase, PubMed, and MEDLINE databases were searched for articles describing artificial intelligence or machine learning healthcare applications with community involvement in model development, validation, or implementation. Model architecture and performance, the nature of community engagement, and barriers or facilitators to community engagement were reported according to PRISMA extension for Scoping Reviews guidelines. Of approximately 10,880 articles describing artificial intelligence healthcare applications, 21 (0.2%) described community involvement. All articles derived data from community settings, most commonly by leveraging existing datasets and sources that included community subjects, and often bolstered by internet-based data acquisition and subject recruitment. Only one article described inclusion of community stakeholders in designing an application-a natural language processing model that detected cases of likely child abuse with 90% accuracy using harmonized electronic health record notes from both hospital and community practice settings. The primary barrier to including community-derived data was small sample sizes, which may have affected 11 of the 21 studies (53%), introducing substantial risk for overfitting that threatens generalizability. Community engagement in artificial intelligence healthcare application development, validation, or implementation is rare. As healthcare delivery occurs primarily in community settings, investigators should consider engaging community stakeholders in user-centered design, usability, and clinical implementation studies to optimize generalizability.

Permeable pavements are vital in sustainable urban water management, addressing critical challenges while enhancing environmental resilience. This study focuses on the innovative polyurethane-bound Porous Rubber Pavement (PRP), which possesses high permeability and elasticity due to its unique composition of stone and crumb rubber aggregates with polyurethane binders. PRP’s useful benefits, such as noise reduction, efficient snow/ice management, and others, enhance its appeal, emphasizing the necessity for a thorough investigation into its performance and characteristics, especially in North America. To address these gaps, this paper comprehensively analyzes PRP’s durability and performance, including its strength range, failure criteria, and susceptibility to moisture-induced damage. Various testing methods are utilized, such as evaluating the abrasion loss of the stone aggregate, rutting, stripping due to moisture susceptibility, resistance to degradation from impact and abrasion, and permeability tests. This study evaluates five distinct mix compositions with varied proportions of aggregates and binders. Further, it investigates the effects of different binder types on PRP performance, such as aromatic and aliphatic binders obtained from various sources. Upon the analysis of the comprehensive test results, it was found that the mix characterized by increased rubber aggregates and a high binder content demonstrated a superior performance across various tests for PRP applications. This mix exhibited an enhanced resistance to abrasion, raveling, rutting, and permanent deformation, showcasing its durability and functionality. Additionally, when combined with an aliphatic binder, it displayed an optimal performance even in challenging freeze–thaw conditions, making it a recommended choice for long-term pavement solutions.

Abstract Zika virus (ZIKV) infection during pregnancy poses significant threats to maternal and fetal health, leading to intrauterine fetal demise and severe developmental malformations that constitute congenital Zika syndrome (CZS). As such, the development of a safe and effective ZIKV vaccine is a critical public health priority. However, the safety and efficacy of such a vaccine during pregnancy remain uncertain. Historically, the conduct of clinical trials in pregnant women has been challenging. Therefore, clinically relevant animal pregnancy models are in high demand for testing vaccine efficacy. We previously reported that a marmoset pregnancy model of ZIKV infection consistently demonstrated vertical transmission from mother to fetus during pregnancy. Using this marmoset model, we also showed that vertical transmission could be prevented by pre-pregnancy vaccination with Zika purified inactivated virus (ZPIV) vaccine. Here, we further examined the efficacy of ZPIV vaccination during pregnancy. Vaccination during pregnancy elicited virus neutralizing antibody responses that were comparable to those elicited by pre-pregnancy vaccination. Vaccination also reduced placental pathology, viral burden and vertical transmission of ZIKV during pregnancy, without causing adverse effects. These results provide key insights into the safety and efficacy of ZPIV vaccination during pregnancy and demonstrate positive effects of vaccination on the reduction of ZIKV infection, an important advance in preparedness for future ZIKV outbreaks.

Abstract Zika virus (ZIKV) is a significant threat to pregnant women and their fetuses as it can cause severe birth defects and congenital neurodevelopmental disorders, referred to as congenital Zika syndrome (CZS). Thus, a safe and effective ZIKV vaccine for pregnant women to prevent in utero ZIKV infection is of utmost importance. Murine models of ZIKV infection are limited by the fact that immunocompetent mice are resistant to ZIKV infection. As such, interferon-deficient mice have been used in some preclinical studies to test the efficacy of ZIKV vaccine candidates against lethal virus challenge. However, interferon-deficient mouse models have limitations in assessing the immunogenicity of vaccines, necessitating the use of immunocompetent mouse pregnancy models. Using the human stat2 knock-in (hSTAT2KI) mouse pregnancy model, we show that vaccination with a purified formalin-inactivated Zika virus (ZPIV) vaccine prior to pregnancy successfully prevented vertical transmission. In addition, maternal immunity protected offspring against postnatal challenge for up to 28 days. Furthermore, passive transfer of human IgG purified from hyper-immune sera of ZPIV vaccinees prevented maternal and fetal ZIKV infection, providing strong evidence that the neutralizing antibody response may serve as a meaningful correlate of protection.

Abstract Background Titanium dioxide nanoparticles (TiO2 NPs) have been reported to have contrasting effects on plant physiology, while their effects on sugar, protein, and amino acid metabolism are poorly understood. In this work, we evaluated the effects of TiO2 NPs on physiological and agronomical traits of tomato (Solanum lycopersicum L.) seedlings. Tomato seeds were treated with TiO2 NPs (1000 and 2000 mg L− 1), TiO2 microparticles (µPs, 2000 mg L− 1) as the size control, and ultrapure water as negative control. Results The dry matter of stems (DMs), leaves (DMl) and total dry matter (DMt) decreased as particle concentration increased. This trend was also observed in the maximum quantum yield of light-adapted photosystem II (PSII) (Fv´/Fm´), the effective quantum yield of PSII (ΦPSII), and net photosynthesis (Pn). The concentrations of sugars, total soluble proteins, and total free amino acids were unaffected, but there were differences in the daily dynamics of these compounds among the treatments. Conclusion Our results suggest that treating tomato seeds with TiO2 might affect PSII performance, net photosynthesis and decrease biomass production, associated with a concentration- and size-related effect of TiO2 particles.

Abstract Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Objective:. To determine whether certain patients are vulnerable to errant triage decisions immediately after major surgery and whether there are unique sociodemographic phenotypes within overtriaged and undertriaged cohorts. Background:. In a fair system, overtriage of low-acuity patients to intensive care units (ICUs) and undertriage of high-acuity patients to general wards would affect all sociodemographic subgroups equally. Methods:. This multicenter, longitudinal cohort study of hospital admissions immediately after major surgery compared hospital mortality and value of care (risk-adjusted mortality/total costs) across 4 cohorts: overtriage (N = 660), risk-matched overtriage controls admitted to general wards (N = 3077), undertriage (N = 2335), and risk-matched undertriage controls admitted to ICUs (N = 4774). K-means clustering identified sociodemographic phenotypes within overtriage and undertriage cohorts. Results:. Compared with controls, overtriaged admissions had a predominance of male patients (56.2% vs 43.1%, P < 0.001) and commercial insurance (6.4% vs 2.5%, P < 0.001); undertriaged admissions had a predominance of Black patients (28.4% vs 24.4%, P < 0.001) and greater socioeconomic deprivation. Overtriage was associated with increased total direct costs [$16.2K ($11.4K–$23.5K) vs $14.1K ($9.1K–$20.7K), P < 0.001] and low value of care; undertriage was associated with increased hospital mortality (1.5% vs 0.7%, P = 0.002) and hospice care (2.2% vs 0.6%, P < 0.001) and low value of care. Unique sociodemographic phenotypes within both overtriage and undertriage cohorts had similar outcomes and value of care, suggesting that triage decisions, rather than patient characteristics, drive outcomes and value of care. Conclusions:. Postoperative triage decisions should ensure equality across sociodemographic groups by anchoring triage decisions to objective patient acuity assessments, circumventing cognitive shortcuts and mitigating bias.

IntroductionEnvironmental exposures and experimental manipulations can alter the ontogenetic composition of tissue-resident macrophages. However, the impact of these alterations on subsequent immune responses, particularly in allergic airway diseases, remains poorly understood. This study aims to elucidate the significance of modified macrophage ontogeny resulting from environmental exposures on allergic airway responses to house dust mite (HDM) allergen.MethodsWe utilized embryonic lineage labeling to delineate the ontogenetic profile of tissue-resident macrophages at baseline and following the resolution of repeated lipopolysaccharide (LPS)-induced lung injury. We investigated differences in house dust mite (HDM)-induced allergy to assess the influence of macrophage ontogeny on allergic airway responses. Additionally, we employed single-cell RNA sequencing (scRNAseq) and immunofluorescent staining to characterize the pulmonary macrophage composition, associated pathways, and tissue localization.ResultsOur findings demonstrate that the ontogeny of homeostatic alveolar and interstitial macrophages is altered after the resolution from repeated LPS-induced lung injury, leading to the replacement of embryonic-derived by bone marrow-derived macrophages. This shift in macrophage ontogeny is associated with reduced HDM-induced allergic airway responses. Through scRNAseq and immunofluorescent staining, we identified a distinct subset of resident-derived interstitial macrophages expressing genes associated with allergic airway diseases, localized adjacent to terminal bronchi, and diminished by prior LPS exposure.DiscussionThese results suggest a pivotal role for pulmonary macrophage ontogeny in modulating allergic airway responses. Moreover, our findings highlight the implications of prior environmental exposures in shaping future immune responses and influencing the development of allergies. By elucidating the mechanisms underlying these phenomena, this study provides valuable insights into potential therapeutic targets for allergic airway diseases and avenues for further research into immune modulation and allergic disease prevention.

IntroductionDespite the necessity for adults with lower literacy skills to undergo and succeed in high-stakes computer-administered assessments (e.g., GED, HiSET), there remains a gap in understanding their engagement with digital literacy assessments.MethodsThis study analyzed process data, specifically time allocation data, from the Program for the International Assessment of Adult Competencies (PIAAC), to investigate adult respondents’ patterns of engagement across all proficiency levels on nine digital literacy items. We used cluster analysis to identify distinct groups with similar time allocation patterns among adults scoring lower on the digital literacy assessment. Finally, we employed logistic regression to examine whether the groups varied by demographic factors, in particular individual (e.g., race/ethnicity, age) and contextual factors (e.g., skills-use at home).ResultsAdults with lower literacy skills spent significantly less time on many of the items than adults with higher literacy skills. Among adults with lower literacy skills, two groups of time allocation patterns emerged: one group (Cluster 1) exhibited significantly longer engagement times, whereas the other group (Cluster 2) demonstrated comparatively shorter durations. Finally, we found that adults who had a higher probability of Cluster 1 membership (spending more time) exhibited relatively higher literacy scores, higher self-reported engagement in writing skills at home, were older, unemployed, and self-identified as Black.DiscussionThese findings emphasize differences in digital literacy engagement among adults with varying proficiency levels. Additionally, this study provides insights for the development of targeted interventions aimed at improving digital literacy assessment outcomes for adults with lower literacy skills.

Objective Gastro-oesophageal reflux disease (GORD) is a common condition affecting children, characterised by the passage of gastric contents into the oesophagus causing pain, vomiting and regurgitation. Children with neurodisability (such as cerebral palsy; CP) are predisposed to more severe GORD due to coexisting gut dysmotility and exclusive/supplementary liquid diet; however, there are no existing tools or outcome measures to assess the severity of GORD in this patient group. For children without CP, the ‘Paediatric Gastro-oesophageal Symptom and Quality of Life Questionnaire’ (PGSQ) assesses symptoms and response to treatment, but the questions are not suitable for children with significant cognitive impairment. We aimed to adapt the existing PGSQ assessment tool to enable use in evaluating children with CP and GORD.Patients/interventions Cognitive interviews were conducted by the research team with six parents/carers of children (aged 3–15) with CP (Gross Motor Function Classification System level V) who have current or past symptoms of reflux. They were asked to interpret the questionnaire using a ‘think-aloud technique,’ and offer suggestions on alterations to questions. Reasons for changing questions included confusing/difficult to understand questions, differing interpretations of questions and response choices not applying to the patient group.Results The PGSQ was modified iteratively following each interview. Overall, parents/carers reported that it was acceptable to recall information over the past 7 days. In the final version, it was felt the questions were relevant, useful and related to symptoms that they observed. It was easy to comprehend with no uncomfortable questions. Suggestions for future work included a section specifically focusing on the school day answered by school staff and home life answered by carers who assist them in the home.Conclusions We have adapted the PGSQ to improve relevance and acceptability for families/carers of children with symptoms of GORD and neurodisability. Further work is needed to validate the questionnaire for this patient group.

AbstractBee propolis has been used in alternative medicine to treat various diseases. Due to its limited water solubility, it is often used in combination with alcohol solvents, causing skin irritation and immune response. To solve this, the new drug delivery system, based on the lipid nanodiscs of 1,2-dimyristoyl-sn-glycero-3-phosphochline (DMPC) and poly(styrene-alt-maleic acid) (PSMA), were created in an aqueous media. At the excess polymer concentrations, the PSMA/DMPC complexation produced the very fine nanoparticles (18 nm). With the increased molar ratio of styrene to maleic acid (St/MA) in the copolymer structure, the lipid nanodisc showed the improved encapsulation efficiency (EE%), comparing to their corresponding aqueous formulations. The maximum value had reached to around 20% when using the 2:1 PSMA precursor. Based on the cytotoxicity test, these nanoparticles were considered to be non-toxic over the low dose administration region (

This study investigates hydrogels based on 2-Acrylamido-2-methyl-1-propanesulfonic acid sodium salt (AMPS) copolymers, incorporating N-hydroxyethyl acrylamide (HEA) and 3-sulfopropyl acrylate potassium salt (SPA). The addition of HEA and SPA is designed to fine-tune the hydrogels’ water absorption and mechanical properties, ultimately enhancing their characteristics and expanding their potential for biomedical applications. A copolymer of AMPS, 2-carboxyethyl acrylate (CEA) combined with methacrylic acid (MAA) as poly(AMPS-stat-CEA-stat-MAA, PACM), was preliminarily synthesized. CEA and MAA were modified with allyl glycidyl ether (AGE) through ring-opening, yielding macromers with pendant allyl groups (PACM-AGE). Copolymers poly(AMPS-stat-HEA-stat-CEA-stat-MAA) (PAHCM) and poly(AMPS-stat-SPA-stat-CEA-stat-MAA) (PASCM) were also synthesized and modified with AGE to produce PAHCM-AGE and PASCM-AGE macromers. These copolymers and macromers were characterized by 1H NMR, FT-IR, and GPC, confirming successful synthesis and functionalization. The macromers were then photocrosslinked into hydrogels and evaluated for swelling, water content, and mechanical properties. The results revealed that the PASCM-AGE hydrogels exhibited superior swelling ratios and water retention, achieving equilibrium water content (~92%) within 30 min. While the mechanical properties of HEA and SPA containing hydrogels show significant differences compared to PACM-AGE hydrogel (tensile strength 2.5 MPa, elongation 47%), HEA containing PAHCM-AGE has a higher tensile strength (5.8 MPa) but lower elongation (19%). In contrast, SPA in the PASCM-AGE hydrogels led to both higher tensile strength (3.7 MPa) and greater elongation (92%), allowing for a broader range of hydrogel properties. An initial study on drug delivery behavior was conducted using PACM-AGE hydrogels loaded with photosensitizers, showing effective absorption, release, and antibacterial activity under light exposure. These AMPS-based macromers with HEA and SPA modifications demonstrate enhanced properties, making them promising for wound management and drug delivery applications.

Objectives: Study objectives were to: (1) better understand sleep experiences and unhealthy alcohol use among Veterans with long COVID and (2) explore providers’ perceptions of barriers and facilitators to delivering evidence-based care for sleep problems and unhealthy alcohol use in patients with long COVID. Methods: VA electronic health records were used to conduct chart reviews (n = 57) of patients evaluated in a VA COVID-19 Recovery Clinic during 1 calendar year; semi-structured interviews were completed with Veterans (n = 5) and clinicians (n = 7) recruited from the clinic. Veteran participants also completed quantitative, self-report measures assessing sleep- and alcohol-related experiences and behaviors. Results: Data from chart reviews and interviews suggested that Veterans with long COVID often had pre-existing sleep problems that were exacerbated during long COVID. Patients and providers agreed that sleep interventions would be beneficial and acceptable in the COVID-19 Recovery clinic. Conversely, few Veterans with long COVID had a pre-existing alcohol use disorder (AUD) diagnosis; alcohol use occurred less frequently and was less often discussed between patients and providers. Providers had mixed viewpoints on delivering alcohol-related care in the clinic; some were highly amenable, others were unsure whether patients would be receptive. Conclusions: This study is among the first to take a mixed-method approach to understanding experiences of sleep-wake behaviors and unhealthy alcohol use in Veterans with long COVID. Characterizing sleep and alcohol-related experiences, examining associations with functioning, and exploring perspectives on treatment approaches is critical to support efforts to refine, personalize, and optimize evidence-based sleep and alcohol care for Veterans living with long COVID.

Microbial diversity estimation involves extracting nucleic acids from intricate sample matrices. Preparing nucleic acid samples is time-consuming, necessitating effective cell lysis and obtaining pure, inhibitor-free nucleic acid purifications before further use. An automated system offers advantages for field deployment due to its ease of use and quick autonomous results. This is especially beneficial for rapid measurement of in situ microbial diversity in remote areas. Our study aimed to assess microbial diversity of Yellowstone hot springs using a field-deployable lab in a resource-limited remote setting and demonstrate on-site nucleic acid sample processing and sequencing. We collected microbial mat and sediment samples from several Yellowstone National Park hot springs, focusing on the Five Sister Springs (FSS), spring LNN010, and Octopus Spring (OS). The samples were processed for DNA extraction on-site and further sequenced in the lab for microbial diversity. In addition, DNA extracted from one sample was sequenced and analyzed on-site as proof-of-concept. Using either Illumina or Oxford Nanopore Technology sequencing, we found similar microbial diversities. Bacteria (over 90%) were predominant at the FSS and OS sites, with archaea accounting for less than 10%. Metagenomic results were taxonomically categorized based on the closest known organism with a sequenced genome. The dominant archaeal community member was Candidatus Caldiarchaeum subterraneum, and among bacteria, Roseiflexus sp. RS-1 was abundant in mat samples. Interestingly, Bacterium HR17 was also frequently found, suggesting the need for more research on this newly recognized bacterial community member. The presence of Bacterium HR17 in these hot springs suggests its potential role in nitrogen cycling, informing both ecological understanding and industrial potential. This pioneering study assessed the microbiome of Yellowstone hot springs in about 8-9 hours using an automated system for nucleic acid extraction. By its deployment, the system’s value in elucidating the microbial diversity of extreme environments without the need to bring samples to the lab for processing had been highlighted. Sample processing and sequencing had been included in the benefits of the field-deployable lab, and the Nanopore platform had been utilized.

Vibration-based damage detection is a range of methods that utilizes the dynamic response of a structure to evaluate its condition and detect damage. It is an important approach for structural health monitoring and has drawn much attention from researchers. While multiple reviews have been published focusing on different aspects of this field, there has not been a study specifically examining the recent development across the range of methods, including natural frequency, mode shape, modal curvature, modal strain energy, and modal flexibility-based damage detection methods. This paper aims to fill this gap by reviewing the recent application of these methods in civil structures, including beams, plates, trusses, frames, and composite structural members. The merits and limitations of each method are discussed, and research opportunities are presented. This broader review also provides an opportunity for critical comparison across this range of methods. While predominantly reviewing experiment-based studies, this review also considers some numerical studies that may motivate further research.

Abstract Background Validated screening tools can be utilised to detect early disease processes and risk factors for disease and adverse outcomes. Consequently, identifying individuals in need of early intervention and targeted assessment can be achieved through the implementation of screening in the ED. Successful implementation can be impacted by a lack of resources and ineffective integration of screening into the clinical workflow. Tailored implementation processes and staff training, which are contextually specific to the ED setting, are facilitators to effective implementation. This review will assist in the identification of barriers and facilitators to screening in the ED using a QES to underpin implementation processes. Healthcare workers engage in screening in the ED routinely. Consequently, this review focused on synthesizing the experience of healthcare workers (HCWs) who are involved in this process. This synthesis is informed by a QES protocol published by the lead author in 2021 (Barry et al., HRB Open Res 3:50, 2021). Methodology A comprehensive literature search, inclusive of grey literature sources, was undertaken. Initially, an a priori framework of themes was formed to facilitate the interpretation and organisation of search results. A context specific conceptual model was then formulated using “Best fit” framework synthesis which further assisted in the interpretation of data that was extracted from relevant studies. Dual blind screening of search results was undertaken using RAYYAN as a platform. Thirty studies were identified that met the inclusion criteria. Dual appraisal of full text articles was undertaken using CASP, GRADE CERQual assessed confidence of findings and data extraction was performed by two reviewers collaboratively. Findings This is the first known synthesis of qualitative research on HCW’s experiences of screening in the ED. Predominantly, the findings illustrate that staff experience screening in the ED as a complex challenging process. The barriers and facilitators identified can be broadly categorised under preconditions to screen, motivations to screen and knowledge and skills to screen. Competing interests in the ED, environmental stressors such as overcrowding and an organisational culture that resists screening were clear barriers. Adequate resources and tailored education to underpin the screening process were clear facilitators. Trial registration PROSPERO: CRD42020188712 05/07/20.

Abstract Shape-morphing robots can change their morphology to fulfill different tasks in varying environments, but existing shape-morphing capability is not embedded in a robot’s body, requiring bulky supporting equipment. Here, we report an embedded shape-morphing scheme with the shape actuation, sensing, and locking, all embedded in a robot’s body. We showcase this embedded scheme using three morphing robotic systems: 1) self-sensing shape-morphing grippers that can adapt to objects for adaptive grasping; 2) a quadrupedal robot that can morph its body shape for different terrestrial locomotion modes (walk, crawl, or horizontal climb); 3) an untethered robot that can morph its limbs’ shape for amphibious locomotion. We also create a library of embedded morphing modules to demonstrate the versatile programmable shapes (e.g., torsion, 3D bending, surface morphing, etc.). Our embedded morphing scheme offers a promising avenue for robots to reconfigure their morphology in an embedded manner that can adapt to different environments on demand.

Marguerite McDonald,1 Susan B Janik,2 Frank W Bowden,3 Amit Chokshi,4 Michael A Singer,5 Sean Tighe,6,7 Olivia G Mead,6 Seema Nanda,8 Mujtaba A Qazi,9 Damon Dierker,10 Adam T Shupe,11 Brittany J McMurren12 1Ophthalmic Consultants of Long Island, Lynbrook, NY, USA; 2Solinsky Eye Care, Kensington, CT, USA; 3Bowden Eye & Associates, Jacksonville, FL, USA; 4Florida Eye Specialists, Jacksonville, FL, USA; 5Medical Center Ophthalmology Associates, San Antonio, TX, USA; 6BioTissue Holdings, Inc, Miami, FL, USA; 7Florida International University Herbert Wertheim College of Medicine, Miami, FL, USA; 8Nanda Dry Eye & Vision Institute, Houston, TX, USA; 9Pepose Vision Institute, Chesterfield, MO, USA; 10Eye Surgeons of Indiana, Indianapolis, IN, USA; 11Royo Eye Care, Marysville, CA, USA; 12Werner Optometry, San Diego, CA, USACorrespondence: Sean Tighe, 7300 Corporate Center Drive, Suite 700, Miami, FL, 33126, USA, Email stighe@biotissue.comBackground: While sutureless, cryopreserved amniotic membrane (cAM) has been shown to significantly improve signs and symptoms of dry eye disease (DED), no studies have assessed the association of cAM treatment duration to the differential response in clinical outcomes.Methods: A multi-center, retrospective study was conducted on patients with moderate-to-severe DED who were treated with self-retained cAM (Prokera® Slim) for 2 to 7 days. The primary outcome measure was DEWS severity score assessed at 1 week, 1 month, and 3 months. Secondary outcome measures included ocular discomfort, visual symptoms, corneal staining, and visual acuity.Results: A total of 89 eyes (77 patients) with moderate-to-severe DED (DEWS severity 3.24 ± 0.56) received treatment with self-retained cAM for 2 days (n = 10), 3 days (n = 15), 4 days (n = 12), 5 days (n = 19), 6 days (n = 6), or 7 days (n = 27). DEWS scores significantly improved at 1 week, 1 month, and 3 months for all treatment duration groups, with no significant difference observed between groups at any timepoint. In addition to an improvement in DEWS severity scores, those receiving cAM treatment for 2 days demonstrated a significant improvement in corneal staining, visual symptoms, and ocular discomfort at 1 week, 1 month, and 3 months.Conclusion: This retrospective study suggests that a single placement of self-retained cAM for 2 days can significantly improve signs and symptoms of DED with a lasting benefit observed for up to 3 months.Keywords: amniotic membrane, cryopreserved, dry eye, ocular surface, Prokera

Resilience assessment of transportation infrastructure is a crucial aspect of ensuring the continued functionality of a city or region in the face of various disruptions. However, these infrastructures are also vulnerable to various types of disruptions, such as natural disasters. The ability of transportation infrastructures to withstand and recover from such disruptions is referred to as their resilience. This research presents a comprehensive framework to develop the resilience surface for assessing the resilience of transportation infrastructure such as bridges, roads, and tunnels. The framework involves the identification of the unique damage configurations through performing the fragility analysis, and the restoration of the infrastructures through developing recovery curves for each damage configuration by considering the relevant restoration data. The framework also considers the inherent uncertainty in the hazard intensity, modeling uncertainty, and restoration process. The framework is illustrated through the application to a case study of a highway bridge in Canada. The aim of this paper is to provide a useful tool for decision-makers to evaluate and improve the resilience of transportation infrastructures.

Epigenetic regulation, notably histone post-translational modification (PTM), has emerged as a major transcriptional control of gene expression during cellular stress adaptation. In the present study, we use an acid extraction method to isolate total histone protein and investigate dynamic changes in 23 well-characterized histone methylations/acetylations in the brains of wood frogs subject to 24-h freezing and subsequent 8-h thawed recovery conditions. Our results identify four histone PTMs (H2BK5ac, H3K14ac, H3K4me3, H3K9me2) and three histone proteins (H1.0, H2B, H4) that were significantly (p < 0.05) responsive to freeze-thaw in freeze-tolerant R. sylvatica brains. Two other permissive modifications (H3R8me2a, H3K9ac) also trended downwards following freezing stress. Together, these data are strongly supportive of the proposed global transcriptional states of hypometabolic freeze tolerance and rebounded thawed recovery. Our findings shed light on the intricate interplay between epigenetic regulation, gene transcription and energy metabolism in wood frogs’ adaptive response to freezing stress.

Boron (B) is a micronutrient crucial for the growth, development, productivity, and quality of crops. However, in areas characterized by acid soil (pHwater < 5.0) and high rainfall, soil B concentration tends to decrease, leading to insufficient supply to crops. This study was aimed at determining the optimal rate of B fertilization to enhance Vaccinium corymbosum L. performance in acid conditions. One-year-old cultivars with contrasting Al resistance (Al-sensitive Star and Al-resistant Cargo) were used. Plants were conditioned in plastic pots containing 18 L of half-ionic-strength Hoagland solution (pH 4.5) for 2 weeks. Thereafter, the following B treatments were applied foliarly: control, without B application (distilled water), 200, 400, and 800 mg L−1 of B as Solubor® for up to 72 h. Photosynthetic performance, root and shoot B levels, antioxidants, and oxidative stress were evaluated. Root and shoot B concentrations increased with the increasing B application, being higher in leaves than in roots of both cultivars. Net photosynthesis decreased at 800 mg L−1 B supply and effective quantum yield of PSII at 72 h in all B treatments. Lipid peroxidation increased in both cultivars at 800 mg L−1 B treatment. Antioxidant activity increased in all B treatments in both cultivars; while, at 400 and 800 mg L−1 B, total phenols increased in leaves of cultivar Star and decreased in cultivar Cargo. In conclusion, optimal B foliar application for highbush blueberry appears to be around 400 mg L−1 B. The appropriate B foliar application could help mitigate potential stress-induced problems in highbush blueberry cultivation. However, the optimal foliar B application should be confirmed in field experiments to help the farmers manage B nutrition.

The importance of environmental consciousness and sustainability is increasing among transportation governing bodies worldwide. Many government bodies are concerned with maximizing the usage of recycled substances in road construction. Therefore, assessing the effect of recycled materials consumption is essential, mainly when designing new ‘green’ pavement types. The primary objective of this study is to investigate the impact of different treatments on improving the interfacial transition zone (ITZ) of coarse recycled concrete aggregate (CRCA) and its application in asphalt mixes. Such an aim is accomplished by enhancing its physical and mechanical characteristics, as well as its microstructure. The surface morphology, chemical composition, and intermix phases of the ITZ area and calcium silicate hydrate (CSH) compounds for CRCA were evaluated using scanning electron microscopy (SEM), an energy-dispersive X-ray analyzer (EDAX), and X-ray diffraction analysis (XRD). The performance of asphalt mixtures that included treated and untreated CRCA was also examined using different tests. It was found that heat treatment is an effective technique for enhancing the ITZ. However, cracks were seen in the mortar of CRCA when exposed to high temperatures (500 °C), which adversely affects the characteristics of the mortar. Acid treatment appeared to be an effective approach for improving the ITZ area. Nevertheless, the treatment that used acetic acid, a weak acid, was more effective than HCl acid, a strong acid. The outcomes revealed that the ITZ microstructure is significantly enhanced under different treatment types; however, microstructure improvements mainly included increased surface homogeneity and CSH compounds and a reduced Ca/Si ratio. It was also found that the asphalt mixtures with different proportions of untreated CRCA exhibited enhanced resistance to rutting. Furthermore, their tensile strength ratio (TSR) values were above the minimal level requirements. Moreover, the asphalt mixture with 30% CRCA, which was treated with various treatment methods, demonstrated a significant improvement in the mixtures’ mechanical properties; therefore, its application is highly successful and an environmentally friendly solution.

Abstract The clock drawing test is a simple and inexpensive method to screen for cognitive frailties, including dementia. In this study, we used the relevance factor variational autoencoder (RF-VAE), a deep generative neural network, to represent digitized clock drawings from multiple institutions using an optimal number of disentangled latent factors. The model identified unique constructional features of clock drawings in a completely unsupervised manner. These factors were examined by domain experts to be novel and not extensively examined in prior research. The features were informative, as they distinguished dementia from non-dementia patients with an area under receiver operating characteristic (AUC) of 0.86 singly, and 0.96 when combined with participants’ demographics. The correlation network of the features depicted the “typical dementia clock” as having a small size, a non-circular or “avocado-like” shape, and incorrectly placed hands. In summary, we report a RF-VAE network whose latent space encoded novel constructional features of clocks that classify dementia from non-dementia patients with high performance.

BackgroundThe World Health Organization 2018 intrapartum guideline for a positive birth experience emphasized the importance of maternal emotional and psychological well-being during pregnancy and the need for safe childbirth. Today, in many countries birth is safe, yet many women report negative and traumatic birth experiences, with adverse effects on their and their families' well-being. Many reviews have attempted to understand the complexity of women's and their partners' birth experience; however, it remains unclear what the key dimensions of the birth experience are.ObjectiveTo synthesize the information from reviews of qualitative studies on the experience of childbirth in order to identify key dimensions of women's and their partners' childbirth experience.MethodsSystematic database searches yielded 40 reviews, focusing either on general samples or on specific modes of birth or populations, altogether covering primary studies from over 35,000 women (and >1000 partners) in 81 countries. We appraised the reviews' quality, extracted data and analysed it using thematic analysis.FindingsFour key dimensions of women's and partners' birth experience (covering ten subthemes), were identified: 1) Perceptions, including attitudes and beliefs; 2) Physical aspects, including birth environment and pain; 3) Emotional challenges; and 4) Relationships, with birth companions and interactions with healthcare professionals. In contrast with the comprehensive picture that arises from our synthesis, most reviews attended to only one or two of these dimensions.ConclusionsThe identified key dimensions bring to light the complexity and multidimensionality of the birth experience. Within each dimension, pathways leading towards negative and traumatic birth experiences as well as pathways leading to positive experiences become tangible. Identifying key dimensions of the birth experience may help inform education and research in the field of birth experiences and gives guidance to practitioners and policy makers on how to promote positive birth experiences for women and their partners.

Background: Research suggests that younger adult African American people (age 18–35 years) have more than double the risk of having a stroke than White people. Stroke risk education is lacking for this cohort; there is a dearth of materials that are targeted and focused for young adult African Americans. There is also little research on developing and testing age and culturally appropriate health literate materials that may help this population better understand personal risk factors for stroke. Objective: The aim of this study was to understand factors to guide creating and disseminating plain language health messages about stroke risk awareness among young adult African Americans. Methods: African American participants age 18 years and older completed an online survey (N = 413). Descriptive statistics, one-way analysis of variance, and two-step cluster analyses were used to evaluate stroke risk awareness, perceived risk of stroke, message creation factors, and online health information seeking behavior. Open-ended survey items described modifiable and non-modifiable reasons for perceived risk of stroke. Key Results: Participants reported differences on overall stroke risk factor awareness by perceived risk of stroke was significant (F[2, 409] = 4.91, p = .008) with the very low/low group (M = 1.66, p < .01), showing significantly lower overall stroke risk factor awareness compared to the moderate and high/very high groups. Both respondents who thought their stroke risk was very low/low and moderate/high/very high commented about family history (54.1% and 45.9%, respectively) as the reason and 88.2% of very low/low commented that they did not have risk factors for stroke because they were young. Cluster analysis indicated the Mostly Clear Preferences cluster was more likely to select mostly/very on positive, informational, and long-term messages and medical authority sources. The largest of three clusters reported medical sources as the highest rated source for both finding and trusting health information (47.2%, n = 195). Conclusion: Young adult African Americans have a scarce understanding of modifiable stroke risk factors; health education materials should focus on positive information messaging that shows a long-term result and is presented by a medical authority. We did not observe any age or sex differences among the data, which suggests different message modalities may not be needed. [HLRP: Health Literacy Research and Practice. 2024;8(1):e38–e46.]

Background There is a growing awareness of the need to include people’s lived experiences in health decision-making. While much progress has been made in this field, exclusionary patterns persist regarding migrant participation in health research. The aim of this scoping review was to examine the available literature around the use of music as an arts-based research (ABR) method in migrant health research in order to extend knowledge of creative methods and tools used for migrant participation in health research. Methods Our review follows a scoping review methodology. Searches were conducted in 11 electronic databases between June and August, 2020. We identified 14 eligible references published between January 2009 and August 2020. We analysed how music is utilised as an arts-based research method in community-based health and wellbeing contexts primarily with refugees, asylum seekers, undocumented migrants, and members of resettled immigrant communities. Results The findings show that music’s role is most prominent as a tool for recruitment and engagement followed by its use as a tool for dissemination. Music is effective as a means to co-produce and communicate knowledge of lived experiences of migration and related wellbeing issues. Recommendations and conclusions Our recommendations for further research include the need for increased detail on the musical element in ABR projects; Explicit identification of such research as ABR; Greater recognition of a multi-arts understanding of music in the context of ABR; Harnessing the potential of music in ABR across the research cycle. We conclude that arts-based research using music shows promise for capturing the complexity of migrants’ lives and health issues in an ethical way. It warrants further investigation in empirical studies in multiple clinical and community settings to understand its processes and impacts on the evidence base for migrant health.

ABSTRACTT cell Receptor (TCR) Fusion Construct (TRuC®) T cells harness all signaling subunits of the TCR to activate T cells and eliminate tumor cells, with minimal release of cytokines. While adoptive cell therapy with chimeric antigen receptor (CAR)-T cells has shown unprecedented clinical efficacy against B-cell malignancies, monotherapy with CAR-T cells has suboptimal clinical efficacy against solid tumors, probably because of the artificial signaling properties of the CAR. TRuC-T cells may address the suboptimal efficacy of existing CAR-T therapies for solid tumors. Here, we report that mesothelin (MSLN)-specific TRuC-T cells (referred to as TC-210 T cells) potently kill MSLN+ tumor cells in vitro and efficiently eradicate MSLN+ mesothelioma, lung, and ovarian cancers in xenograft mouse tumor models. When benchmarked against MSLN-targeted BBζ CAR-T cells (MSLN-BBζ CAR-T cells), TC-210 T cells show an overall comparable level of efficacy; however, TC-210 T cells consistently show faster tumor rejection kinetics that are associated with earlier intratumoral accumulation and earlier signs of activation. Furthermore, in vitro and ex vivo metabolic profiling suggests TC-210 T cells have lower glycolytic activity and higher mitochondrial metabolism than MSLN-BBζ CAR-T cells. These data highlight TC-210 T cells as a promising cell therapy for treating MSLN-expressing cancers. The differentiated profile from CAR-T cells may translate into better efficacy and safety of TRuC-T cells for solid tumors.

Summary: Assignment of biological sex to skeletal remains is critical in the accurate reconstruction of the past. Analysis of sex-chromosome encoded AMELX and AMELY peptides from the enamel protein amelogenin underpins a minimally destructive mass spectrometry (MS) method for sex determination of human remains. However, access to such specialist approaches limits applicability. As a convenient alternative, we generated antibodies that distinguish human AMELX and AMELY. Purified antibodies demonstrated high selectivity and quantitative detection against synthetic peptides by ELISA. Using acid etches of enamel from post-medieval skeletons, antibody determinations corrected osteological uncertainties and matched parallel MS, and for Bronze Age samples where only enamel was preserved, also matched MS analyses. Toward improved throughput, automated stations were applied to analyze 19th-century teeth where sex of individuals was documented, confirming MS can be bypassed. Our immunological tools should underpin development of routine, economical, high-throughput methods for sex determination, potentially even in a field setting.

Abstract Background The Limbal epithelial crypt (LEC) is a solid cord of cells, approximately 120 microns long. It arises from the undersurface of interpalisade rete ridges of the limbal palisades of Vogt and extends deeper into the limbal stroma parallel or perpendicular to the palisade. There are up to 6 or 7 such LEC, variably distributed along the limbus in each human eye. Morphological and immunohistochemical studies on the limbal epithelial crypt (LEC) have demonstrated the presence of limbal stem cells in this region. The purpose of this microarray study was to characterise the transcriptional profile of the LEC and compare with other ocular surface epithelial regions to support our hypothesis that LEC preferentially harbours stem cells (SC). Results LEC was found to be enriched for SC related Gene Ontology (GO) terms including those identified in quiescent adult SC, however similar to cornea, limbus had significant GO terms related to proliferating SC, transient amplifying cells (TAC) and differentiated cells (DC). LEC and limbus were metabolically dormant with low protein synthesis and downregulated cell cycling. Cornea had upregulated genes for cell cycling and self renewal such as FZD7, BTG1, CCNG, and STAT3 which were identified from other SC populations. Upregulated gene expression for growth factors, cytokines, WNT, Notch, TGF-Beta pathways involved in cell proliferation and differentiation were noted in cornea. LEC had highest number of expressed sequence tags (ESTs), downregulated and unknown genes, compared to other regions. Genes expressed in LEC such as CDH1, SERPINF1, LEF1, FRZB1, KRT19, SOD2, EGR1 are known to be involved in SC maintenance. Genes of interest, in LEC belonging to the category of cell adhesion molecules, WNT and Notch signalling pathway were validated with real-time PCR and immunofluorescence. Conclusions Our transcriptional profiling study identifies the LEC as a preferential site for limbal SC with some characteristics suggesting that it could function as a 'SC niche' supporting quiescent SC. It also strengthens the evidence for the presence of "transient cells" in the corneal epithelium. These cells are immediate progeny of SC with self-renewal capacity and could be responsible for maintaining epithelial turn over in normal healthy conditions of the ocular surface (OS). The limbus has mixed population of differentiated and undifferentiated cells.

Abstract Background Microbial dysbiosis is a potential mediator of air pollution-induced adverse outcomes. However, a systemic comparison of the lung and gut microbiome alterations and lung-gut axis following air pollution exposure is scant. In this study, we exposed male C57BL/6J mice to inhaled air, CB (10 mg/m3), O3 (2 ppm) or CB + O3 mixture for 3 h/day for either one day or four consecutive days and were euthanized 24 h post last exposure. The lung and gut microbiome were quantified by 16 s sequencing. Results Multiple CB + O3 exposures induced an increase in the lung inflammatory cells (neutrophils, eosinophils and B lymphocytes), reduced absolute bacterial load in the lungs and increased load in the gut. CB + O3 exposure was more potent as it decreased lung microbiome alpha diversity just after a single exposure. CB + O3 co-exposure uniquely increased Clostridiaceae and Prevotellaceae in the lungs. Serum short chain fatty acids (SCFA) (acetate and propionate) were increased significantly only after CB + O3 co-exposure. A significant increase in SCFA producing bacterial families (Ruminococcaceae, Lachnospiraceae, and Eubacterium) were also observed in the gut after multiple exposures. Co-exposure induced significant alterations in the gut derived metabolite receptors/mediator (Gcg, Glp-1r, Cck) mRNA expression. Oxidative stress related mRNA expression in lungs, and oxidant levels in the BALF, serum and gut significantly increased after CB + O3 exposures. Conclusion Our study confirms distinct gut and lung microbiome alterations after CB + O3 inhalation co-exposure and indicate a potential homeostatic shift in the gut microbiome to counter deleterious impacts of environmental exposures on metabolic system.

Abstract Background Interactions between air pollution and infectious agents are increasingly recognized and critical to identify, especially to protect vulnerable populations. Pregnancy represents a vulnerable period for influenza infection and air pollution exposure, yet interactions during pregnancy remain unclear. Maternal exposure to ultrafine particles (UFPs, $$\le$$ ≤ 100 nm diameter), a class of particulate matter ubiquitous in urban environments, elicits unique pulmonary immune responses. We hypothesized that UFP exposure during pregnancy would lead to aberrant immune responses to influenza enhancing infection severity. Results Building from our well-characterized C57Bl/6N mouse model employing daily gestational UFP exposure from gestational day (GD) 0.5–13.5, we carried out a pilot study wherein pregnant dams were subsequently infected with Influenza A/Puerto Rico/8/1934 (PR8) on GD14.5. Findings indicate that PR8 infection caused decreased weight gain in filtered air (FA) and UFP-exposed groups. Co-exposure to UFPs and viral infection led to pronounced elevation in PR8 viral titer and reduced pulmonary inflammation, signifying potential suppression of innate and adaptive immune defenses. Pulmonary expression of the pro-viral factor sphingosine kinase 1 (Sphk1) and pro-inflammatory cytokine interleukin-1β (IL-1 $$\beta$$ β ) was significantly increased in pregnant mice exposed to UFPs and infected with PR8; expression correlated with higher viral titer. Conclusions Results from our model provide initial insight into how maternal UFP exposure during pregnancy enhances respiratory viral infection risk. This model is an important first step in establishing future regulatory and clinical strategies for protecting pregnant women exposed to UFPs.

Acute lung injury (ALI) is a syndrome of acute inflammation, barrier disruption, and hypoxemic respiratory failure associated with high morbidity and mortality. Diverse conditions lead to ALI, including inhalation of toxic substances, aspiration of gastric contents, infection, and trauma. A shared mechanism of acute lung injury is cellular toxicity from damage-associated molecular patterns (DAMPs), including extracellular histones. We recently described the selection and efficacy of a histone-binding RNA aptamer (HBA7). The current study aimed to identify the effects of extracellular histones in the lung and determine if HBA7 protected mice from ALI. Histone proteins decreased metabolic activity, induced apoptosis, promoted proinflammatory cytokine production, and caused endothelial dysfunction and platelet activation in vitro. HBA7 prevented these effects. The oropharyngeal aspiration of histone proteins increased neutrophil and albumin levels in bronchoalveolar lavage fluid (BALF) and precipitated neutrophil infiltration, interstitial edema, and barrier disruption in alveoli in mice. Similarly, inhaling wood smoke particulate matter, as a clinically relevant model, increased lung inflammation and alveolar permeability. Treatment by HBA7 alleviated lung injury in both models of ALI. These findings demonstrate the pulmonary delivery of HBA7 as a nucleic acid-based therapeutic for ALI.

Abstract Myeloma patients presenting with renal failure continue to have a poor prognosis despite significant advances in anti‐myeloma therapy. MERIT was a randomised clinical trial (RCT), set up to evaluate if mechanical reduction of elevated free light chain levels (FLC) would result in clinical benefit. Completion of the planned seven plasma exchanges (PEs) in the first 14 days failed to show, for the exchange group, a greater reduction in FLC or any improvement in dialysis independence at 100 days or subsequently. To improve prognosis for these patients requires earlier diagnosis and prompt anti‐myeloma therapy with effectiveness guided by frequent FLC monitoring.

PURPOSE: To assess the extent of inferior fornix shortening in conjunctivochalasis (CCh) and to evaluate whether fornix deepening reconstruction can restore the fornix tear reservoir in patients with CCh. MATERIALS AND METHODS: This was a retrospective review of five patients (3 unilateral and 2 bilateral eyes, total 7 eyes) with CCh who underwent fornix deepening reconstruction with conjunctival recession and amniotic membrane transplantation. Postsurgical outcome measures included changes in fornix depth with correlation to basal tear volumes, symptoms, corneal staining, and conjunctival inflammation. RESULTS: For the three patients with unilateral surgery, both the fornix depth (8.3 ± 1.5 mm) and wetting length (9.3 ± 8.5 mm) of the operative eyes were less than the fellow eyes (10.3 ± 1.5 mm and 10.3 ± 8.5 mm, respectively). At 5.3 ± 2.7 months (range 1.7–8.7) postoperatively, the fornix depth increased significantly by 2.0 ± 1.1 mm (P = 0.02). Deepening of the fornix depth was accompanied by overwhelming symptomatic relief (91.5%) that could be subdivided into complete relief (87.5%) and partial relief (4%) of symptoms, with blurred vision being the most notably relieved symptom (P = 0.03). Furthermore, superficial punctate keratitis and conjunctival inflammation were significantly improved at follow-up (P = 0.008 and 0.05, respectively). CONCLUSION: Deepening of the fornix to restore the tear reservoir is an important surgical objective that may change the tear hydrodynamic state to provide a stable tear film and improve outcomes in CCh.

Abstract Lake Hillier is a hypersaline lake known for its distinctive bright pink color. The cause of this phenomenon in other hypersaline sites has been attributed to halophiles, Dunaliella, and Salinibacter, however, a systematic analysis of the microbial communities, their functional features, and the prevalence of pigment-producing-metabolisms has not been previously studied. Through metagenomic sequencing and culture-based approaches, our results evidence that Lake Hillier is composed of a diverse set of microorganisms including archaea, bacteria, algae, and viruses. Our data indicate that the microbiome in Lake Hillier is composed of multiple pigment-producer microbes, including Dunaliella, Salinibacter, Halobacillus, Psychroflexus, Halorubrum, many of which are cataloged as polyextremophiles. Additionally, we estimated the diversity of metabolic pathways in the lake and determined that many of these are related to pigment production. We reconstructed complete or partial genomes for 21 discrete bacteria (N = 14) and archaea (N = 7), only 2 of which could be taxonomically annotated to previously observed species. Our findings provide the first metagenomic study to decipher the source of the pink color of Australia’s Lake Hillier. The study of this pink hypersaline environment is evidence of a microbial consortium of pigment producers, a repertoire of polyextremophiles, a core microbiome and potentially novel species.

Abstract Bacteria in the Shigella genus remain a major cause of dysentery in sub-Saharan Africa, and annually cause an estimated 600,000 deaths worldwide. Being spread by contaminated food and water, this study highlights how wild caught food, in the form of freshwater catfish, can act as vectors for Shigella flexneri in Southern Kenya. A metatranscriptomic approach was used to identify the presence of Shigella flexneri in the catfish which had been caught for consumption from the Galana river. The use of nanopore sequencing was shown to be a simple and effective method to highlight the presence of Shigella flexneri and could represent a potential new tool in the detection and prevention of this deadly pathogen. Rather than the presence/absence results of more traditional testing methods, the use of metatranscriptomics highlighted how primarily one SOS response gene was being transcribed, suggesting the bacteria may be dormant in the catfish. Additionally, COI sequencing of the vector catfish revealed they likely represent a cryptic species. Morphological assignment suggested the fish were widehead catfish Clarotes laticeps, which range across Africa, but the COI sequences from the Kenyan fish are distinctly different from C. laticeps sequenced in West Africa.

BackgroundSuicide is a global public health problem. Digital interventions are considered a low-threshold treatment option for people with suicidal ideation or behaviors. Internet-based cognitive behavioral therapy (iCBT) targeting suicidal ideation has demonstrated effectiveness in reducing suicidal ideation. However, suicidal ideation often is related to additional mental health problems, which should be addressed for optimal care. Yet, the effects of iCBT on related symptoms, such as depression, anxiety, and hopelessness, remain unclear. ObjectiveWe aimed to analyze whether digital interventions targeting suicidal ideation had an effect on related mental health symptoms (depression, anxiety, and hopelessness). MethodsWe systematically searched CENTRAL, PsycInfo, Embase, and PubMed for randomized controlled trials that investigated guided or unguided iCBT for suicidal ideation or behaviors. Participants reporting baseline suicidal ideation were eligible. Individual participant data (IPD) were collected from eligible trials. We conducted a 1-stage IPD meta-analysis on the effects on depression, anxiety, and hopelessness—analyzed as 2 indices: symptom severity and treatment response. ResultsWe included IPD from 8 out of 9 eligible trials comprising 1980 participants with suicidal ideation. iCBT was associated with significant reductions in depression severity (b=−0.17; 95% CI −0.25 to −0.09; P

Introduction Human papillomavirus (HPV) is necessary but not sufficient for cervical cancer development. During cervical carcinogenesis, methylation levels increase across host and HPV DNA. DNA methylation has been proposed as a test to diagnose cervical intraepithelial neoplasia (CIN); we present a protocol to evaluate the accuracy of methylation markers to detect high-grade CIN and cervical cancer.Methods and analysis We will search electronic databases (Medline, Embase and Cochrane Library), from inception, to identify studies examining DNA methylation as a diagnostic marker for CIN or cervical cancer, in a cervical screening population. The primary outcome will be to assess the diagnostic test accuracy of host and HPV DNA methylation for high-grade CIN; the secondary outcomes will be to examine the accuracy of different methylation cut-off thresholds, and accuracy in high-risk HPV positive women. Our reference standard will be histology. We will perform meta-analyses using Cochrane guidelines for diagnostic test accuracy. We will use the number of true positives, false negatives, true negatives and false positives from individual studies. We will use the bivariate mixed effect model to estimate sensitivity and specificity with 95% CIs; we will employ different bivariate models to estimate sensitivity and specificity at different thresholds if sufficient data per threshold. For insufficient data, the hierarchical summary receiver operating curve model will be used to calculate a summary curve across thresholds. If there is interstudy and intrastudy variation in thresholds, we will use a linear mixed effects model to calculate the optimum threshold. If few studies are available, we will simplify models by assuming no correlation between sensitivity and specificity and perform univariate, random-effects meta-analysis. We will assess the quality of studies using QUADAS-2 and QUADAS-C.Ethics and dissemination Ethical approval is not required. Results will be disseminated to academic beneficiaries, medical practitioners, patients and the public.PROSPERO registration number CRD42022299760.

Geosynthetic materials have been widely used to enhance engineering practice in buildings, bridges, and pavements. As a kind of popular stabilization product, geogrid can be used for pavement reinforcement by serving as an additional tensile element. It has been demonstrated by many laboratory studies and numerical simulations that the reinforcement could significantly extend the fatigue life and improve the rutting resistance in flexible pavement. Meanwhile, geotextiles can provide soil separation, filtration and drainage; therefore, mitigating the freeze-thaw disturbances in the subgrade underneath the pavement structure. To study the application of geosynthetics in pavement structures in a more comprehensive aspect, a full-scale study was performed. A fibreglass geogrid which is specifically designed to reinforce the asphalt layer; as well as a geogrid composite material made of bi-axial geogrid bonded to a continuous filament non-woven geotextile, were installed in two field test sections. The geogrid was installed in the middle of the binder course within the asphalt layer, while the geogrid composite was placed at the interface of the base layer and subgrade in another section. The stiffness of the pavement was tested on each layer of the pavement structure during construction. As one of the major criteria to evaluate the pavement condition in North America, the International Roughness Index (IRI) was assessed to investigate the performances of geosynthetic-reinforced pavement during construction on asphalt binder course and surface course.

Permanent deformation, or rutting, is one of several critical distresses in flexible pavements. This paper introduced a novel experimental method, a penetration test, for asphalt mixtures to quantify the effects of glass fibre geogrids embedded in asphalt under repeated loading. It was found that the evolution of permanent deformation (εp) and its strain rate have three clearly identifiable stages. It was also observed that the presence of the geogrid increased the flow number and the number of cycles to failure significantly compared to control samples. Some of the current εp fitting models were found to be valid for deformation prediction under penetration. In addition, a new simple FN calculation method was also proposed based on strain rate and it showed consistent results. In particular, geogrid type “Grid10”, which has smaller aperture size (12.7 mm) had slightly better reinforcement performance regarding the rutting resistance due to its larger contact area. Overall, the test and data analysis method presented in this study could be an important reference for future investigations on geosynthetic-reinforced pavement materials.