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Abstract Disorder in crystals is rarely random, and instead involves local correlations whose presence and nature are hidden from conventional crystallographic probes. This hidden order can sometimes be controlled, but its importance for physical properties of materials is not well understood. Using simple models for electronic and interatomic interactions, we show how crystals with identical average structures but different types of hidden order can have very different electronic and phononic band structures. Increasing the strength of local correlations within hidden-order states can open band gaps and tune mode (de)localisation—both mechanisms allowing for fundamental changes in physical properties without long-range symmetry breaking. Taken together, our results demonstrate how control over hidden order offers a new mechanism for tuning material properties, orthogonal to the conventional principles of (ordered) structure/property relationships.

Abstract Babesiosis is a disease of significant medically and veterinary importance with worldwide distribution. It is caused by intra-erythrocyte protozoal parasites, with Babesia rossi causing the most severe clinical signs of all the large Babesia parasites infecting dogs. The disease can be clinically classified into uncomplicated and complicated forms with a wide range of clinical presentations from a mild, subclinical illness to complicated forms and death. The aim of this study was to assess serum proteomic profiles from dogs with babesiosis and healthy dogs using a label-based proteomics approach. Altogether 32 dogs naturally infected with B. rossi (subdivided into 18 uncomplicated cases and 14 complicated cases of babesiosis) and 20 healthy dogs were included. There were 78 proteins with significantly different abundances between the three groups of dogs. Elucidation of proteins and pathways involved in canine babesiosis caused by B. rossi have revealed key differences associated with haemostasis, innate immune system, lipid metabolism and inflammation. Shotgun proteomic profiling allowed identification of potential serum biomarkers for differentiation of disease severity in canine babesiosis caused by B. rossi. These findings may be applicable to the study of host-parasite interactions and the development of novel therapeutic targets.

BackgroundMany emerging adults (EAs) are prone to making unhealthy choices, which increase their risk of premature cancer morbidity and mortality. In the era of social media, rigorous research on interventions to promote health behaviors for cancer risk reduction among EAs delivered over social media is limited. Cancer prevention information and recommendations may reach EAs more effectively over social media than in settings such as health care, schools, and workplaces, particularly for EAs residing in rural areas. ObjectiveThis pragmatic randomized trial aims to evaluate a multirisk factor intervention using a social media campaign designed with community advisers aimed at decreasing cancer risk factors among EAs. The trial will target EAs from diverse backgrounds living in rural counties in the Four Corners states of Arizona, Colorado, New Mexico, and Utah. MethodsWe will recruit a sample of EAs (n=1000) aged 18 to 26 years residing in rural counties (Rural-Urban Continuum Codes 4 to 9) in the Four Corners states from the Qualtrics’ research panel and enroll them in a randomized stepped-wedge, quasi-experimental design. The inclusion criteria include English proficiency and regular social media engagement. A social media intervention will promote guideline-related goals for increased physical activity, healthy eating, and human papillomavirus vaccination and reduced nicotine product use, alcohol intake, and solar UV radiation exposure. Campaign posts will cover digital and media literacy skills, responses to misinformation, communication with family and friends, and referral to community resources. The intervention will be delivered over 12 months in Facebook private groups and will be guided by advisory groups of community stakeholders and EAs and focus groups with EAs. The EAs will complete assessments at baseline and at 12, 26, 39, 52, and 104 weeks after randomization. Assessments will measure 6 cancer risk behaviors, theoretical mediators, and participants’ engagement with the social media campaign. ResultsThe trial is in its start-up phase. It is being led by a steering committee. Team members are working in 3 subcommittees to optimize community engagement, the social media intervention, and the measures to be used. The Stakeholder Organization Advisory Board and Emerging Adult Advisory Board were formed and provided initial input on the priority of cancer risk factors to target, social media use by EAs, and community resources available. A framework for the social media campaign with topics, format, and theoretical mediators has been created, along with protocols for campaign management. ConclusionsSocial media can be used as a platform to counter misinformation and improve reliable health information to promote health behaviors that reduce cancer risks among EAs. Because of the popularity of web-based information sources among EAs, an innovative, multirisk factor intervention using a social media campaign has the potential to reduce their cancer risk behaviors. Trial RegistrationClinicalTrials.gov NCT05618158; https://classic.clinicaltrials.gov/ct2/show/NCT05618158 International Registered Report Identifier (IRRID)PRR1-10.2196/50392

ABSTRACT Millions suffer from urinary tract infections (UTIs) worldwide every year with women accounting for the majority of cases. Uropathogenic Escherichia coli (UPEC) causes most of these primary infections and leads to 25% becoming recurrent or chronic. To repel invading pathogens, the urinary tract mounts a vigorous innate immune response that includes the secretion of antimicrobial peptides (AMPs), rapid recruitment of phagocytes, and exfoliation of superficial umbrella cells. Here, we investigate secretory leukocyte protease inhibitor (SLPI), an AMP with antiprotease, antimicrobial, and immunomodulatory functions, known to play protective roles at other mucosal sites, but not well characterized in UTIs. Using a preclinical model of UPEC-caused UTI, we show that urine SLPI increases in infected mice and that SLPI is localized to bladder epithelial cells. UPEC-infected SLPI-deficient (Slpi−/−) mice suffer from higher urine bacterial burdens, prolonged bladder inflammation, and elevated urine neutrophil elastase (NE) levels compared to wild-type (Slpi+/+) controls. Combined with bulk bladder RNA sequencing, our data indicate that Slpi−/− mice have a dysregulated immune and tissue repair response following UTI. We also measure SLPI in urine samples from a small group of female subjects 18–49 years old and find that SLPI tends to be higher in the presence of a uropathogen, except in patients with a history of recent or recurrent UTI, suggesting a dysregulation of SLPI expression in these women. Taken together, our findings show SLPI promotes clearance of UPEC in mice and provides preliminary evidence that SLPI is likewise regulated in response to uropathogen exposure in women.IMPORTANCEAnnually, millions of people suffer from urinary tract infections (UTIs) and more than $3 billion are spent on work absences and treatment of these patients. While the early response to UTI is known to be important in combating urinary pathogens, knowledge of host factors that help curb infection is still limited. Here, we use a preclinical model of UTI to study secretory leukocyte protease inhibitor (SLPI), an antimicrobial protein, to determine how it protects the bladder against infection. We find that SLPI is increased during UTI, accelerates the clearance of bacteriuria, and upregulates genes and pathways needed to fight an infection while preventing prolonged bladder inflammation. In a small clinical study, we show SLPI is readily detectable in human urine and is associated with the presence of a uropathogen in patients without a previous history of UTI, suggesting SLPI may play an important role in protecting from bacterial cystitis.

Many if not most of us watched in utter disbelief and horror last September 11th as Aaron Rogers, the newly acquired $75 million dollar quarterback with the New York Jets just 4 snaps into the new season, suffered an Achilles Tendon ruptures (ATR) in his inaugural game on nationally televised Monday Night Football with his new and excited team and demanding fanbase. With cell phones in hand, we watched as our X apps lit up with claims of an excess of ATRs in the NFL in recent years and much of the blame placed on the new rubberized turf surfaces in place in most of the NFL stadiums. That first week of the NFL season the NFL Players Association, the NFLPA, put out a statement to this effect that demanded removal of rubberized turf surfaces throughout the NFL! With Kirk Cousins devastating ATR a few weeks later, amongst 21 others this season, and Aaron Rogers return to practice after a mere seven to eight weeks post-injury, this conundrum remains foremost in our hyper-questioning minds!

Abstract Objective: To examine the association between red and processed meat consumption and total food expenditures in US households and explore whether households could reduce food costs by substituting these meats with other protein sources such as poultry, seafood, eggs and plant proteins. Design: Cross-sectional study using data from the National Household Food Acquisition and Purchase Survey (FoodAPS). Using adult male equivalents (AME) for standardisation, we categorised red and processed meat purchases into quintiles. We used generalised linear models to explore the association between red or processed meat consumption and food expenditures and the cost effect of substituting meat with other proteins. Setting: United States. Participants: Data from 4739 households with valid acquisition information from FoodAPS, a stratified multistage probability sample of US households. Results: Higher red and processed meat consumption were both significantly associated with higher total weekly food expenditures, particularly among households with low income. Substituting red or processed meat with poultry, eggs or plant proteins did not significantly affect overall food expenditures, whereas replacing meat with seafood, especially varieties high in n-3 fatty acids, led to increased costs. Conclusions: Reducing red and processed meat consumption could offer savings for households, particularly those with low income. Although substitutions with seafood high in n-3 could increase expenses, alternative protein sources like poultry and plant proteins may serve as cost-neutral replacements. Public health strategies should emphasise dietary shifts’ economic, health and environmental benefits and aim to make nutritious yet affordable protein sources more accessible.

Stable isotope data have made pivotal contributions to nearly every discipline of the physical and natural sciences. As the generation and application of stable isotope data continues to grow exponentially, so does the need for a unifying data repository to improve accessibility and promote collaborative engagement. This paper provides an overview of the design, development, and implementation of IsoBank (www.isobank.org), a community-driven initiative to create an open-access repository for stable isotope data implemented online in 2021. A central goal of IsoBank is to provide a web-accessible database supporting interdisciplinary stable isotope research and educational opportunities. To achieve this goal, we convened a multi-disciplinary group of over 40 analytical experts, stable isotope researchers, database managers, and web developers to collaboratively design the database. This paper outlines the main features of IsoBank and provides a focused description of the core metadata structure. We present plans for future database and tool development and engagement across the scientific community. These efforts will help facilitate interdisciplinary collaboration among the many users of stable isotopic data while also offering useful data resources and standardization of metadata reporting across eco-geoinformatics landscapes.

Analysis of stable isotopes in consumers is used commonly to study their ecological and/or environmental niche. There is, however, considerable debate regarding how isotopic values relate to diet and how other sources of variation confound this link, which can undermine the utility. From the analysis of a simple, but general, model of isotopic incorporation in consumer organisms, we examine the relationship between isotopic variance among individuals, and diet variability within a consumer population. We show that variance in consumer isotope values is directly proportional to variation in diet (through Simpson indices), to the number of isotopically distinct food sources in the diet, and to the baseline variation within and among the isotope values of the food sources. Additionally, when considering temporal diet variation within a consumer we identify the interplay between diet turnover rates and tissue turnover rates that controls the sensitivity of stable isotopes to detect diet variation. Our work demonstrates that variation in the stable isotope values of consumers reflect variation in their diet. This relationship, however, can be confounded with other factors to the extent that they may mask the signal coming from diet. We show how simple quantitative corrections can recover a direct 1:1 correlation in some situations, and in others we can adjust our interpretation in light of the new understanding arising from our models. Our framework provides guidance for the design and analysis of empirical studies where the goal is to infer niche width from stable isotope data.

In multiple studies, we found that people who are viewed as possessing a stronger desire for status are, ironically, afforded lower status by others. Coworkers who were viewed as having a higher (versus lower) desire for status (Study 1a and 1b), and individuals who were described as having a higher desire for status (versus a lower desire for status or no information), were afforded lower status (Studies 2, 3a, and 3b). Mediation analyses and an experimental manipulation of the mediator (Study 3a and 3b) suggested that the observed negative effect of desire for status on status was mediated primarily by perceptions of low prosociality. These findings have important implications for status organizing processes in groups.

Background Recent trials suggest that programmed cell death 1 (PD-1)-directed immunotherapy may be beneficial for some patients with anal squamous cell carcinoma and biomarkers predictive of response are greatly needed.Methods This multicenter phase II clinical trial (NCT02919969) enrolled patients with metastatic or locally advanced incurable anal squamous cell carcinoma (n=32). Patients received pembrolizumab 200 mg every 3 weeks. The primary endpoint of the trial was objective response rate (ORR). Exploratory objectives included analysis of potential predictive biomarkers including assessment of tumor-associated immune cell populations with multichannel immunofluorescence and analysis of circulating tumor tissue modified viral-human papillomavirus DNA (TTMV-HPV DNA) using serially collected blood samples. To characterize the clinical features of long-term responders, we combined data from our prospective trial with a retrospective cohort of patients with anal cancer treated with anti-PD-1 immunotherapy (n=18).Results In the phase II study, the ORR to pembrolizumab monotherapy was 9.4% and the median progression-free survival was 2.2 months. Despite the high level of HPV positivity observed with circulating TTMV-HPV DNA testing, the majority of patients had low levels of tumor-associated CD8+PD-1+ T cells on pretreatment biopsy. Patients who benefited from pembrolizumab had decreasing TTMV-HPV DNA scores and a complete responder’s TTMV-HPV DNA became undetectable. Long-term pembrolizumab responses were observed in one patient from the trial (5.3 years) and three patients (2.5, 6, and 8 years) from the retrospective cohort. Long-term responders had HPV-positive tumors, lacked liver metastases, and achieved a radiological complete response.Conclusions Pembrolizumab has durable efficacy in a rare subset of anal cancers. However, despite persistence of HPV infection, indicated by circulating HPV DNA, most advanced anal cancers have low numbers of tumor-associated CD8+PD-1+ T cells and are resistant to pembrolizumab.

IntroductionAdvances in the field of genetic testing have spurred its use in transplantation. Potential benefits of genetic testing in transplant nephrology include diagnosis, treatment, risk stratification of recurrent disease, and risk stratification in potential donors. However, it is unclear how to best apply genetic testing in this population to maximize its yield. We describe our transplant center's approach to selective genetic testing as part of kidney transplant candidate and donor evaluation.MethodsTransplant recipient candidates were tested if they had a history of ESRD at age

ABSTRACTMammals exhibit daily fasting and feeding patterns that produce a fluctuating environment in the gut. By colonizing germfree mice with Bacteroides thetaiotaomicron and examining gene expression through a time-restricted feeding cycle, we demonstrate that this prominent gut commensal exhibits gene expression patterns characteristic of a stringent response and increases ppGpp levels during the host-fasting phase of the feeding regimen. Mutants unable to produce (p)ppGpp fail to produce this transcriptional response, exhibit unrestrained chromosomal replication, and cannot maintain population size during the host-fasting phase. Additionally, B. thetaiotaomicron requires (p)ppGpp to utilize host glycans both in vitro and in vivo, and mutants unable to produce (p)ppGpp display deficiencies in mucus layer colonization during the host-fasting phase. Complete gut microbial communities from mice and humans also increase ppGpp levels in this manner, demonstrating that this response appears to be general across species and conserved across mammalian gut communities. Together, these results identify an intracellular signal that allows gut microbes to coordinate their physiology with a time-restricted feeding regimen of their host.IMPORTANCEMammals do not eat continuously, instead concentrating their feeding to a restricted portion of the day. This behavior presents the mammalian gut microbiota with a fluctuating environment with consequences for host-microbiome interaction, infection risk, immune response, drug metabolism, and other aspects of health. We demonstrate that in mice, gut microbes elevate levels of an intracellular signaling molecule, (p)ppGpp, during the fasting phase of a time-restricted feeding regimen. Disabling this response in a representative human gut commensal species significantly reduces colonization during this host-fasting phase. This response appears to be general across species and conserved across mammalian gut communities, highlighting a pathway that allows healthy gut microbiomes to maintain stability in an unstable environment.

The Candida albicans genome contains between ten and fifteen distinct TLO genes that all encode a Med2 subunit of Mediator. In order to investigate the biological role of Med2/Tlo in C. albicans we deleted all fourteen TLO genes using CRISPR-Cas9 mutagenesis. ChIP-seq analysis showed that RNAP II localized to 55% fewer genes in the tloΔ mutant strain compared to the parent, while RNA-seq analysis showed that the tloΔ mutant exhibited differential expression of genes required for carbohydrate metabolism, stress responses, white-opaque switching and filamentous growth. Consequently, the tloΔ mutant grows poorly in glucose- and galactose-containing media, is unable to grow as true hyphae, is more sensitive to oxidative stress and is less virulent in the wax worm infection model. Reintegration of genes representative of the α-, β- and γ-TLO clades resulted in the complementation of the mutant phenotypes, but to different degrees. TLOα1 could restore phenotypes and gene expression patterns similar to wild-type and was the strongest activator of glycolytic and Tye7-regulated gene expression. In contrast, the two γ-TLO genes examined (i.e., TLOγ5 and TLOγ11) had a far lower impact on complementing phenotypic and transcriptomic changes. Uniquely, expression of TLOβ2 in the tloΔ mutant stimulated filamentous growth in YEPD medium and this phenotype was enhanced when Tloβ2 expression was increased to levels far in excess of Med3. In contrast, expression of reintegrated TLO genes in a tloΔ/med3Δ double mutant background failed to restore any of the phenotypes tested, suggesting that complementation of these Tlo-regulated processes requires a functional Mediator tail module. Together, these data confirm the importance of Med2/Tlo in a wide range of C. albicans cellular activities and demonstrate functional diversity within the gene family which may contribute to the success of this yeast as a coloniser and pathogen of humans.

ABSTRACT Interactions between humans, animals, and the environment are considered critical foci for addressing antimicrobial resistance (AMR). However, One Health data on AMR in low- and middle-income countries are presently scarce. Using metagenomics, we investigated whether and how the fecal antibiotic resistomes of humans are influenced by exposure to intensive and non-intensively reared poultry within contrasting settings of urban wet markets (n = 13) and rural households (n = 7) in Bangladesh. We also considered poultry (n = 10) and wastewater (n = 10) resistomes in these settings. We found that occupational poultry exposures did not significantly alter the human fecal resistome. In contrast, macrolide-lincosamide-streptogramin and streptothricin antibiotic resistance genes (ARGs) were enriched in poultry from urban wet markets relative to rural household chickens. Wastewater had the highest ARG richness, though this was only partially explained by poultry cecal and human fecal sources. Wastewater also contained clinically significant carbapenem ARGs. This study therefore provides critical insight into the distribution of ARGs in Bangladesh. IMPORTANCE Through the use of DNA sequencing, our study shows that there is no significant difference in the antibiotic resistance genes found in stool samples taken from individuals with high exposure to poultry routinely fed antibiotics and those without such exposure. This finding is significant as it suggests limited transmission of antibiotic resistance genes between poultry and humans in these circumstances. However, our research also demonstrates that commercially reared poultry are more likely to possess resistance genes to antibiotics commonly administered on medium-sized farms. Additionally, our study highlights the under-explored potential of wastewater as a source of various antibiotic resistance genes, some of which are clinically relevant.

Dense, cold waters formed on Antarctic continental shelves descend along the Antarctic continental margin, where they mix with other Southern Ocean waters to form Antarctic Bottom Water (AABW). AABW then spreads into the deepest parts of all major ocean basins, isolating heat and carbon from the atmosphere for centuries. Despite AABW’s key role in regulating Earth’s climate on long time scales and in recording Southern Ocean conditions, AABW remains poorly observed. This lack of observational data is mostly due to two factors. First, AABW originates on the Antarctic continental shelf and slope where in situ measurements are limited and ocean observations by satellites are hampered by persistent sea ice cover and long periods of darkness in winter. Second, north of the Antarctic continental slope, AABW is found below approximately 2 km depth, where in situ observations are also scarce and satellites cannot provide direct measurements. Here, we review progress made during the past decades in observing AABW. We describe 1) long-term monitoring obtained by moorings, by ship-based surveys, and beneath ice shelves through bore holes; 2) the recent development of autonomous observing tools in coastal Antarctic and deep ocean systems; and 3) alternative approaches including data assimilation models and satellite-derived proxies. The variety of approaches is beginning to transform our understanding of AABW, including its formation processes, temporal variability, and contribution to the lower limb of the global ocean meridional overturning circulation. In particular, these observations highlight the key role played by winds, sea ice, and the Antarctic Ice Sheet in AABW-related processes. We conclude by discussing future avenues for observing and understanding AABW, impressing the need for a sustained and coordinated observing system.

Abstract How to identify follicular lymphoma (FL) patients with low disease burden but high risk for early progression is unclear. Building on a prior study demonstrating the early transformation of FLs with high variant allele frequency (VAF) BCL2 mutations at activation-induced cytidine deaminase (AICDA) sites, we examined 11 AICDA mutational targets, including BCL2, BCL6, PAX5, PIM1, RHOH, SOCS, and MYC, in 199 newly diagnosed grade 1 and 2 FLs. BCL2 mutations with VAF ≥20% occurred in 52% of cases. Among 97 FL patients who did not initially receive rituximab-containing therapy, nonsynonymous BCL2 mutations at VAF ≥20% were associated with increased transformation risk (HR 3.01, 95% CI 1.04–8.78, p = 0.043) and a trend toward shorter event-free survival (EFS, median 20 months with mutations versus 54 months without, p = 0.052). Other sequenced genes were less frequently mutated and did not increase the prognostic value of the panel. Across the entire population, nonsynonymous BCL2 mutations at VAF ≥20% were associated with decreased EFS (HR 1.55, 95% CI 1.02–2.35, p = 0.043 after correction for FLIPI and treatment) and decreased overall survival after median 14-year follow-up (HR 1.82, 95% CI 1.05–3.17, p = 0.034). Thus, high VAF nonsynonymous BCL2 mutations remain prognostic even in the chemoimmunotherapy era.

Abstract The pet trade is known to be one of the most important pathways of aquatic non-native species introduction and Indonesia is a significant trade partner. Popular ornamental South American river stingrays (Potamotrygon spp.) were introduced to Indonesia in the 1980s and the culture was established. Here we present a detailed Indonesian market and aquaculture survey, the volume of trade between January 2020 and June 2022, and the list of customer countries with the total amount of imported stingrays. Climate similarities between the native range of P. motoro and P. jabuti and Indonesia were analysed. A significant number of areas of Indonesian islands were identified as suitable for the establishment of this species. This was confirmed by the first record of probably established populations in the Brantas River (Java). In total 13 individuals including newborns were captured. The culture of potamotrygonid stingrays is unregulated in Indonesia, and the risk of the establishment of this predator and its potential spread is alarming for wildlife. Moreover, the first case of envenomation caused by Potamotrygon spp. in the wild outside of South America was recorded. The current condition is predicted as the ‘tip of the iceberg’ and continuous monitoring and mitigation of risks are strongly recommended.

Abstract Bacterial cell growth and division require the coordinated action of enzymes that synthesize and degrade cell wall polymers. Here, we identify enzymes that cleave the d-arabinan core of arabinogalactan, an unusual component of the cell wall of Mycobacterium tuberculosis and other mycobacteria. We screened 14 human gut-derived Bacteroidetes for arabinogalactan-degrading activities and identified four families of glycoside hydrolases with activity against the d-arabinan or d-galactan components of arabinogalactan. Using one of these isolates with exo-d-galactofuranosidase activity, we generated enriched d-arabinan and used it to identify a strain of Dysgonomonas gadei as a d-arabinan degrader. This enabled the discovery of endo- and exo-acting enzymes that cleave d-arabinan, including members of the DUF2961 family (GH172) and a family of glycoside hydrolases (DUF4185/GH183) that display endo-d-arabinofuranase activity and are conserved in mycobacteria and other microbes. Mycobacterial genomes encode two conserved endo-d-arabinanases with different preferences for the d-arabinan-containing cell wall components arabinogalactan and lipoarabinomannan, suggesting they are important for cell wall modification and/or degradation. The discovery of these enzymes will support future studies into the structure and function of the mycobacterial cell wall.

Background: Cannabis use may adversely affect cardiovascular health. Patterns of use by cardiac patients are unknown. We evaluated the prevalence, perceptions, and patterns of cannabis use among cardiac inpatients. Methods: A consecutive cross-section of cardiac inpatients, hospitalized between November 2019 and May 2020, were surveyed in-person or via telephone. Descriptive statistics and logistic regression were used to examine the characteristics of cannabis use. Results: The prevalence of past-12-month cannabis use was 13.8% (95% confidence interval [CI]: 11.8%-16.0%). Characteristics independently associated with cannabis use were as follows: age < 64 years (< 44 years, odds ratio [OR] = 3.96 [95% CI: 1.65-9.53]; age 45-64 years, OR = 2.72 [95% CI: 1.65-4.47]); tobacco use in the previous 6 months (OR = 1.91 [95% CI: 1.18-3.07]); having a cannabis smoker in one’s primary social group (OR = 4.17 [95% CI: 2.73-6.38]); and a history of a mental health diagnosis (OR = 1.82 [95% CI: 1.19-2.79]). Among those using cannabis, 70.5% reported smoking or vaping it; 47.2% reported daily use. Most did not know the tetrahydrocannabinol (THC; 71.6%) or cannabidiol (CBD; 83.3%) content of their cannabis, or the dose of cannabis in their edibles (66.7%). As defined by Canada’s Lower Risk Cannabis Use Guidelines, 96.7% of cannabis users reported ≥ 1 higher-risk use behaviour (mean = 2.3, standard deviation = 1.2). Over 60% of patients expressed no intention to quit or reduce cannabis use in the next 6 months. Conclusions: Cannabis use appears prevalent among cardiac patients. Most users demonstrated higher-risk use behaviours and low intentions to quit. Further work is needed to understand the impacts of cannabis use on the cardiovascular system and to develop guidelines and educational tools relating to lower-risk use, for cardiac patients and providers. RÉsumÉ: Contexte: L’utilisation du cannabis peut nuire à la santé cardiovasculaire, mais les habitudes d’utilisation des patients atteints de troubles cardiaques ne sont pas connues. Nous avons évalué la prévalence, les perceptions et les habitudes d’utilisation du cannabis chez des patients hospitalisés présentant des troubles cardiaques. Méthodologie: Une analyse transversale a été réalisée en interrogeant en personne ou au téléphone des patients hospitalisés consécutivement entre novembre 2019 et mai 2020 et présentant des troubles cardiaques. Des statistiques descriptives et une régression logistique ont été utilisées pour examiner les caractéristiques liées à l’utilisation du cannabis. Résultats: La prévalence de l’utilisation du cannabis au cours des 12 mois précédents était de 13,8 % (intervalle de confiance [IC] à 95 % : 11,8 % à 16,0 %). Les caractéristiques indépendamment associées à l’utilisation du cannabis étaient les suivantes : âge < 64 ans (< 44 ans, rapport de cotes [RC] = 3,96 [IC à 95 % : 1,65 à 9,53]; âge de 45 à 64 ans, RC = 2,72 [IC à 95 % : 1,65 à 4,47]); tabagisme dans les six mois précédents (RC = 1,91 [IC à 95 % : 1,18 à 3,07]); présence d’un consommateur de cannabis au sein du cercle social principal (RC = 4,17 [IC à 95 % : 2,73 à 6,38]); et diagnostic antérieur lié à la santé mentale (RC = 1,82 [IC à 95 % : 1,19 à 2,79]). Parmi les utilisateurs de cannabis, 70,5 % d’entre eux ont rapporté qu’ils fumaient ou vapotaient et 47,2 % ont déclaré en consommer quotidiennement. La plupart ne connaissaient pas le contenu en tétrahydrocannabinol (THC; 71,6 %) ou en cannabidiol (CBD; 83,3 %) du cannabis consommé, ou la dose contenue dans les aliments à base de cannabis consommés (66,7 %). Au total, 96,7 % des utilisateurs de cannabis ont rapporté ≥ 1 comportement(s) à risque élevé (moyenne = 2,3, écart-type = 1,2) selon les Recommandations canadiennes pour l’usage du cannabis à moindre risque. Par ailleurs, plus de 60 % des patients n’ont exprimé aucune intention d’interrompre ou de diminuer leur consommation de cannabis au cours des six prochains mois. Conclusions: L’utilisation du cannabis semble courante chez les patients qui présentent des troubles cardiaques. La plupart des utilisateurs ont démontré des comportements à risque élevé, et une faible intention de mettre fin à leur consommation. D’autres études sont requises pour caractériser les répercussions de l’utilisation du cannabis sur l’appareil cardiovasculaire et élaborer des lignes directrices et des outils éducatifs à l’intention des patients atteints de troubles cardiaques et des professionnels de la santé en vue de favoriser un usage à moindre risque.

In the midwestern United States, especially Missouri, winegrape (Vitis sp.) growers mostly plant interspecific hybrids, which are well adapted to the climate and pests of the region. ‘Chambourcin’ (an interspecific French-American hybrid) is one of the most widely planted winegrape cultivars in the area. It is usually grown as own-rooted (nongrafted) vines because the economic and horticultural benefits of grafting this cultivar to rootstocks have not been well developed. Further, few significant winegrape rootstock evaluations have been conducted in the midwestern United States, including evaluations of newer rootstocks developed and released by private and public breeding programs. The aim of this study was to assess the potential value of using rootstocks in ‘Chambourcin’ production in southern Missouri, with implications for the midwestern United States. Fruit yield, vine growth, and fruit composition metrics from ‘Chambourcin’ on 10 different root systems [own-rooted, and grafted to rootstocks ‘Couderc 3309’, ‘Couderc 1616’, ‘Paulsen 1103’, ‘Sélection Oppenheim 4’, ‘Millardet et de Grasset 420A’, ‘Millardet et de Grasset 101-14’, ‘Kingfisher’, ‘Matador’ (all Vitis sp.), and ‘Gloire de Montpellier’ riverbank grape (Vitis riparia)] in an experimental vineyard in southwest Missouri were compared. Following three establishment years (2008–10), data were collected across four growing and vintage seasons (2011–14). Yield components evaluated included total fruit production, clusters per vine, cluster weight, berry weight, weight of cane prunings, and crop load. Petiole mineral analysis was conducted in 2011, 2013, and 2014. Grape juice attributes measured were soluble solids concentration, juice pH, titratable acidity (TA), potassium (K), anthocyanins, tannins, phenolics, and organic acids. When simply comparing grafted vs. ungrafted vines, grafting generally induced higher plant vigor and a higher pH in the juice, whereas the other parameters did not differ. When the performances were compared among the 10 root systems, vines grafted to ‘Couderc 3309’ had higher yields compared with vines grafted to six other rootstocks and own-rooted vines. Grafting to ‘Millardet et de Grasset 101-14’ induced higher cluster weight compared with the other rootstocks. The ‘Millardet et de Grasset 420A’ rootstock promoted a higher pH and TA as well as a higher concentration of K in the juice, and ‘Paulsen 1103’ also promoted high pH, TA, and malic acid in the juice, and higher concentrations of phosphorous (P) and K in the petiole compared with most rootstocks. ‘Gloire de Montpellier’ induced a lower P content in the petiole and a higher tartaric/malic acid ratio. Rootstock use can strongly influence some vineyard production metrics as well as nutrient uptake and K levels in the juice (the latter further influencing juice pH). The results of this study provide insights into the complex viticultural and enological interactions resulting from the use of rootstocks in hybrid winegrape production in Missouri, USA.

In a cohort of essential workers in the United States previously infected with SARS-CoV-2, risk factors for reinfection included being unvaccinated, infrequent mask use, time since first infection, and being non-Hispanic Black. Protecting workers from reinfection requires a multipronged approach including up-to-date vaccination, mask use as recommended, and reduction in underlying health disparities.

Nanostructures synthesised by hard-templating assisted methods are advantageous as they retain the size and morphology of the host templates which are vital characteristics for their intended applications. A number of techniques have been employed to deposit materials inside porous templates, such as electrodeposition, vapour deposition, lithography, melt and solution filling, but most of these efforts have been applied with pore sizes higher in the mesoporous regime or even larger. Here, we explore atomic layer deposition (ALD) as a method for nanostructure deposition into mesoporous hard templates consisting of mesoporous silica films with sub-5 nm pore diameters. The zinc oxide deposited into the films was characterised by small-angle X-ray scattering, X-ray diffraction and energy-dispersive X-ray analysis.

Connexins (Cxs) are a family of integral membrane proteins, which function as both hexameric hemichannels (HCs) and dodecameric gap junction channels (GJCs), behaving as conduits for the electrical and molecular communication between cells and between cells and the extracellular environment, respectively. Their proper functioning is crucial for many processes, including development, physiology, and response to disease and trauma. Abnormal GJC and HC communication can lead to numerous pathological states including inflammation, skin diseases, deafness, nervous system disorders, and cardiac arrhythmias. Over the last 15 years, high-resolution X-ray and electron cryomicroscopy (cryoEM) structures for seven Cx isoforms have revealed conservation in the four-helix transmembrane (TM) bundle of each subunit; an αβ fold in the disulfide-bonded extracellular loops and inter-subunit hydrogen bonding across the extracellular gap that mediates end-to-end docking to form a tight seal between hexamers in the GJC. Tissue injury is associated with cellular Ca2+ overload. Surprisingly, the binding of 12 Ca2+ ions in the Cx26 GJC results in a novel electrostatic gating mechanism that blocks cation permeation. In contrast, acidic pH during tissue injury elicits association of the N-terminal (NT) domains that sterically blocks the pore in a “ball-and-chain” fashion. The NT domains under physiologic conditions display multiple conformational states, stabilized by protein–protein and protein–lipid interactions, which may relate to gating mechanisms. The cryoEM maps also revealed putative lipid densities within the pore, intercalated among transmembrane α-helices and between protomers, the functions of which are unknown. For the future, time-resolved cryoEM of isolated Cx channels as well as cryotomography of GJCs and HCs in cells and tissues will yield a deeper insight into the mechanisms for channel regulation. The cytoplasmic loop (CL) and C-terminal (CT) domains are divergent in sequence and length, are likely involved in channel regulation, but are not visualized in the high-resolution X-ray and cryoEM maps presumably due to conformational flexibility. We expect that the integrated use of synergistic physicochemical, spectroscopic, biophysical, and computational methods will reveal conformational dynamics relevant to functional states. We anticipate that such a wealth of results under different pathologic conditions will accelerate drug discovery related to Cx channel modulation.

Despite data showing that nutritional interventions high in antioxidant/anti-inflammatory properties (anthocyanin-rich foods, such as blueberries/elderberries) may decrease risk of memory loss and cognitive decline, evidence for such effects in mild cognitive impairment (MCI) is limited. This study examined preliminary effects of American elderberry (Sambucus nigra subsp. canadensis) juice on cognition and inflammatory markers in patients with MCI. In a randomized, double-blind, placebo–controlled trial, patients with MCI (n = 24, Mage = 76.33 ± 6.95) received American elderberry (n = 11) or placebo (n = 13) juice (5 mL orally 3 times a day) for 6 months. At baseline, 3 months, and 6 months, patients completed tasks measuring global cognition, verbal memory, language, visuospatial cognitive flexibility/problem solving, and memory. A subsample (n = 12, 7 elderberry/5 placebo) provided blood samples to measure serum inflammatory markers. Multilevel models examined effects of the condition (elderberry/placebo), time (baseline/3 months/6 months), and condition by time interactions on cognition/inflammation outcomes. Attrition rates for elderberry (18%) and placebo (15%) conditions were fairly low. The dosage compliance (elderberry—97%; placebo—97%) and completion of cognitive (elderberry—88%; placebo—87%) and blood-based (elderberry—100%; placebo—100%) assessments was high. Elderberry (not placebo) trended (p = 0.09) towards faster visuospatial problem solving performance from baseline to 6 months. For the elderberry condition, there were significant or significantly trending decreases over time across several markers of low-grade peripheral inflammation, including vasorin, prenylcysteine oxidase 1, and complement Factor D. Only one inflammatory marker showed an increase over time (alpha-2-macroglobin). In contrast, for the placebo, several inflammatory marker levels increased across time (L-lactate dehydrogenase B chain, complement Factor D), with one showing deceased levels over time (L-lactate dehydrogenase A chain). Daily elderberry juice consumption in patients with MCI is feasible and well tolerated and may provide some benefit to visuospatial cognitive flexibility. Preliminary findings suggest elderberry juice may reduce low-grade inflammation compared to a placebo–control. These promising findings support the need for larger, more definitive prospective studies with longer follow-ups to better understand mechanisms of action and the clinical utility of elderberries for potentially mitigating cognitive decline.

The genus Dichichthys was resurrected for five species previously allocated to the genus Parmaturus in the family Pentanchidae. Supraorbital crests on the chondrocranium distinguish Dichichthys from Parmaturus and other members of the family Pentanchidae. A new family, Dichichthyidae, has been proposed to contain Dichichthys. The sequence of the NADH2 mitochondrial gene confirms the placement of Dichichthys outside of the Pentanchidae family, as well as separate from the Atelomycteridae and Scyliorhinidae families. Dichichthys albimarginatus was described using a holotype collected off the coast of New Caledonia. A second juvenile specimen collected off the coast of Papua New Guinea was tentatively assigned as D. cf. albimarginatus. Dichichthys bigus is known from the holotype collected in the Coral Sea off the coast of Queensland, Australia. A new, parasite-afflicted underwater observation was reported further north of Queensland. The type species Dichichthys melanobranchus, previously only known from juvenile specimens, was redescribed based on adult specimens. Dichichthys nigripalatum is known from the holotype collected off Sumbawa, Indonesia, and a tentatively identified photo record from West Java. Dichichthys satoi n. sp. is described from the West Norfolk Ridge and off the North Island of New Zealand. Members of the genus Dichichthys have unique curved egg cases which have pliable ridges made up of numerous fibres and long coiled tendrils on the posterior end.

We have previously shown that in the developing trunk of zebrafish embryos, two-pore channel type 2 (TPC2)-mediated Ca 2+ release from endolysosomes plays a role in the formation of the skeletal slow muscle. In addition, TPC2-mediated Ca 2+ signaling is required for axon extension and the establishment of synchronized activity in the primary motor neurons. Here, we report that TPC2 might also play a role in the development of the notochord of zebrafish embryos. For example, when tpcn2 was knocked down or out, increased numbers of small vacuoles were formed in the inner notochord cells, compared with the single large vacuole in the notochord of control embryos. This abnormal vacuolation was associated with embryos displaying attenuated body axis straightening. We also showed that TPC2 has a distinct pattern of localization in the notochord in embryos at ∼24 hpf. Finally, we conducted RNAseq to identify differentially expressed genes in tpcn2 mutants compared to wild-type controls, and found that those involved in actin filament severing, cellular component morphogenesis, Ca 2+ binding, and structural constituent of cytoskeleton were downregulated in the mutants. Together, our data suggest that TPC2 activity plays a key role in notochord biogenesis in zebrafish embryos.

Introduction: Ruthenium(II) complexes have emerged recently as candidates for anti-cancer therapy, where activity is related to lipohilicity, cellular localization, and specific interactions with biomolecules.Methods: In this work, two novel complexes were synthesized and are reported based on the [Ru(phen)2(dipyrido[3,2-f:2′,3′-h]quinoxaline]2+ framework.Results: Compared to the parent complex, annealing of cyclopenteno and cyclohexeno rings to the extended ligand substantially increased cytotoxicity towards a number of cancer cell lines, and induced apoptosis. The complexes localize in the nuclei of cancer cells and co-locate with DAPI on DNA. DNA binding studies show that both complexes bind strongly to DNA and one complex intercalates DNA like the parent, whilst the other appears to have multiple modes of interaction.Discussion: It is likely that the increased lipophilicity of the novel complexes is a key factor for increasing their cytotoxicity, rather than their DNA binding mode.

ABSTRACT Linezolid is an antibiotic used to treat serious Staphylococcus aureus infections. Resistance to linezolid is considered rare but could emerge with repeated dosing. We recently reported widespread prescription of linezolid for a cohort of patients with cystic fibrosis (CF). The goals of this study were to determine the incidence of linezolid-resistant methicillin-resistant Staphylococcus aureus (MRSA) in CF and identify molecular mechanisms for linezolid resistance. We identified patients who cultured S. aureus resistant to linezolid with minimum inhibitory concentration (MIC) >4 at the University of Iowa CF Center between 2008 and 2018. We obtained isolates from these patients and retested susceptibility to linezolid using broth microdilution. We used whole genome sequencing to perform phylogenetic analysis of linezolid-resistant isolates and examine sequences for mutations or accessory genes that confer linezolid resistance. Between 2008 and 2018, 111 patients received linezolid, and 4 of these patients cultured linezolid-resistant S. aureus. We sequenced 11 resistant and 21 susceptible isolates from these 4 subjects. Phylogenetic analysis indicated that linezolid resistance developed in ST5 or ST105 backgrounds. Three individuals had linezolid-resistant S. aureus with a G2576T mutation in 23S rRNA. One of these subjects additionally had a mutS− mutL− hypermutating S. aureus that produced five resistant isolates with multiple ribosomal subunit mutations. In one subject, the genetic basis for linezolid resistance was unclear. We conclude that linezolid resistant S. aureus can occur through multiple genetic mechanisms in patients with repeated exposure to this antibiotic. IMPORTANCE Patients with cystic fibrosis have persistent lung infections with Staphylococcus aureus that require extensive antibiotic treatments. Linezolid, an antibiotic given by oral or intravenous route, is prescribed repeatedly for patients whose lung disease has progressed. After treatment with linezolid, S. aureus strains can evolve antibiotic resistance through multiple genetic mechanisms. In addition to a common mutation in the 23S ribosomal RNA known to confer linezolid resistance, S. aureus strains can evolve novel resistance based on a combination of mutations affecting the bacterial ribosome. This combination of mutations was observed in a strain that exhibited hypermutation owing to the loss of the DNA repair genes mutS and mutL. In this cohort of patients with cystic fibrosis, linezolid resistance was transient, possibly due to the growth disadvantage of resistant strains. However, ongoing chronic exposure to linezolid may create optimal conditions for the future emergence of resistance to this critical antibiotic.

BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental condition commonly studied in the context of early childhood. As ASD is a life-long condition, understanding the characteristics of brain microstructure from adolescence into adulthood and associations to clinical features is critical for improving outcomes across the lifespan. In the current work, we utilized Tract Based Spatial Statistics (TBSS) and Gray Matter Based Spatial Statistics (GBSS) to examine the white matter (WM) and gray matter (GM) microstructure in neurotypical (NT) and autistic males.MethodsMulti-shell diffusion MRI was acquired from 78 autistic and 81 NT males (12-to-46-years) and fit to the DTI and NODDI diffusion models. TBSS and GBSS were performed to analyze WM and GM microstructure, respectively. General linear models were used to investigate group and age-related group differences. Within the ASD group, relationships between WM and GM microstructure and measures of autistic symptoms were investigated.ResultsAll dMRI measures were significantly associated with age across WM and GM. Significant group differences were observed across WM and GM. No significant age-by-group interactions were detected. Within the ASD group, positive relationships with WM microstructure were observed with ADOS-2 Calibrated Severity Scores.ConclusionUsing TBSS and GBSS our findings provide new insights into group differences of WM and GM microstructure in autistic males from adolescence into adulthood. Detection of microstructural differences across the lifespan as well as their relationship to the level of autistic symptoms will deepen to our understanding of brain-behavior relationships of ASD and may aid in the improvement of intervention options for autistic adults.

Abstract Minimal research has been conducted relating apparent electrical conductivity (ECa) surveys to plant and terrain properties in agroforestry systems. Objectives were to identify: (i) ECa–forage yield, –tree growth, and –terrain attribute relationships within ECa‐derived soil management zones (SMZs) and (ii) terrain attributes that drive ECa variability within a 20‐year‐old, 4.25‐ha, agroforestry system in the Ozark Highlands of northwest Arkansas. The average of 12 monthly perpendicular (PRP) and horizontal coplanar (HCP) ECa surveys (August 2020 to July 2021) and 14 terrain attributes were obtained. Tree diameter at breast height (DBH) and height (TH) measurements were made in December 2020 and March 2021, respectively, and forage yield samples were collected during Summer 2018 and 2019. Apparent EC‐tree property relationships were generally stronger within the whole site (averaged across tree property and ECa configuration, |r| = 0.38) than within the SMZs (averaged across tree property, ECa configuration, and SMZ, |r| = 0.27). The strength of the SMZs’ terrain‐attribute‐PRP‐ECa relationships were 9% to 205% greater than that for the whole site. In whole‐site, multi‐linear regressions, slope length and steepness factor (10.5%), mid‐slope (9.4%), and valley depth (7.2%) had the greatest influence (i.e., percent of total sum of squares) on PRP ECa variability, whereas valley depth (15.3%), wetness index (11.9%), and mid‐slope (11.2%) had the greatest influence on HCP ECa variability. Results show how ECa relates to plant (i.e., DBH, TH, and forage yield) and terrain data within SMZs in agroforestry systems with varying topography and could be used to precisely manage agroforestry systems.

Introduction: Ski jumping (SJ) and Nordic combined (NC) athletes are at higher risk for femoroacetabular impingement (FAI) compared to the general population. Objectives: The purpose of this study was to determine the relationship between force plate testing metrics, Functional Movement Screen (FMS) scores, and radiographic signs of FAI and SJ performance. Methods: Elite SJ and NC athletes were prospectively recruited. FMS testing was performed to assess muscular imbalance, instability, and immobility. Vertical jump testing was performed using a commercially available force plate device. Ski jump score and distance score were measured on a single jump for each athlete. Results: Twenty-one athletes (10 SJ, 11 NC) with competition scores were included. On FMS testing, most SJ (67%) and NC (73%) athletes demonstrated core instability. There were higher rates of hip instability and ankle stiffness among SJ athletes, although not statistically significant (P > .05). Ski jump distance score was significantly positively correlated with force plate vertical jump height, maximum acceleration, maximum velocity, concentric impulse, counter-movement depth, and flight time (P

Abstract Complement proteins are deposited in the muscles of patients with myositis. However, the local expression and regulation of complement genes within myositis muscle have not been well characterized. In this study, bulk RNA sequencing (RNAseq) analyses of muscle biopsy specimens revealed that complement genes are locally overexpressed and correlate with markers of myositis disease activity, including the expression of interferon-gamma (IFNγ)-induced genes. Single cell and single nuclei RNAseq analyses showed that most local expression of complement genes occurs in macrophages, fibroblasts, and satellite cells, with each cell type expressing different sets of complement genes. Biopsies from immune-mediated necrotizing myopathy patients, who have the lowest levels of IFNγ-induced genes, also had the lowest complement gene expression levels. Furthermore, data from cultured human cells showed that IFNγ upregulates complement expression in macrophages, fibroblasts, and muscle cells. Taken together, our results suggest that in myositis muscle, IFNγ coordinates the local overexpression of complement genes that occurs in several cell types.

Background: Excess flexion or extension during occipitocervical fusion (OCF) can lead to postoperative complications, such as dysphagia, respiratory problems, line of sight issues, and neck pain, but posterior fossa decompression (PFD) and OCF require different positions that require intraoperative manipulation. Objective: The objective of this study was to describe quantitative fluoroscopic morphometrics in Chiari malformation (CM) patients with symptoms of craniocervical instability (CCI) and demonstrate the intraoperative application of these measurements to achieve neutral craniocervical alignment while leveraging a single axis of motion with the Mayfield head clamp locking mechanism. Methods: A retrospective cohort study of patients with CM 1 and 1.5 and features of CCI who underwent PFD and OCF at a single-center institution from March 2015 to October 2020 was performed. Patient demographics, preoperative presentation, radiographic morphometrics, operative details, complications, and clinical outcomes were analyzed. Results: A total of 39 patients met the inclusion criteria, of which 37 patients (94.9%) did not require additional revision surgery after PFD and OCF. In this nonrevision cohort, preoperative to postoperative occipital to C2 angle (O-C2a) (13.5° ± 10.4° vs. 17.5° ± 10.1°, P = 0.047) and narrowest oropharyngeal airway space (nPAS) (10.9 ± 3.4 mm vs. 13.1 ± 4.8 mm, P = 0.007) increased significantly. These measurements were decreased in the two patients who required revision surgery due to postoperative dysphagia (mean difference – 16.6°° in O C2a and 12.8°° in occipital and external acoustic meatus to axis angle). Based on these results, these fluoroscopic morphometrics are intraoperatively assessed, utilizing a locking Mayfield head clamp repositioning maneuver to optimize craniocervical alignment prior to rod placement from the occipital plate to cervical screws. Conclusion: Establishing a preoperative baseline of reliable fluoroscopic morphometrics can guide surgeons intraoperatively in appropriate patient realignment during combined PFD and OCF, and may prevent postoperative complications.

Abstract Endometriosis is a pathological condition of the female reproductive tract characterized by the existence of endometrium-like tissue at ectopic sites, affecting 10% of women between the age 15 and 49 in the USA. However, currently there is no reliable non-invasive method to detect the presence of endometriosis without surgery and many women find hormonal therapy and surgery as ineffective in avoiding the recurrences. There is a lack of knowledge on the etiology and the factors that contribute to the development of endometriosis. A growing body of recent evidence suggests an association between gut microbiota and endometriosis pathophysiology. However, the direct impact of microbiota and microbiota-derived metabolites on the endometriosis disease progression is largely unknown. To understand the causal role of gut microbiota and endometriosis, we have implemented a novel model using antibiotic-induced microbiota-depleted (MD) mice to investigate the endometriosis disease progression. Interestingly, we found that MD mice showed reduced endometriotic lesion growth and, the transplantation of gut microbiota by oral gavage of feces from mice with endometriosis rescued the endometriotic lesion growth. Additionally, using germ-free donor mice, we indicated that the uterine microbiota is dispensable for endometriotic lesion growth in mice. Furthermore, we showed that gut microbiota modulates immune cell populations in the peritoneum of lesions-bearing mice. Finally, we found a novel signature of microbiota-derived metabolites that were significantly altered in feces of mice with endometriosis. Finally, we found one the altered metabolite, quinic acid promoted the survival of endometriotic epithelial cells in vitro and lesion growth in vivo, suggesting the disease-promoting potential of microbiota-derived metabolites. In summary, these data suggest that gut microbiota and microbiota-derived metabolome contribute to lesion growth in mice, possibly through immune cell adaptations. Of translational significance, these findings will aid in designing non-invasive diagnostics using stool metabolites for endometriosis.

Abstract Background Evidence suggests that dental anxiety and phobia are frequently the result of direct associative fear conditioning but that pre-exposure to dental stimuli prior to conditioning results in latent inhibition of fear learning. The mechanisms underlying the pre-exposure effect in humans, however, are poorly understood. Moreover, pain sensitivity has been linked to dental fear conditioning in correlational investigations and theory suggests it may moderate the latent inhibition effect, but this hypothesis has not been directly tested. These gaps in our understanding are a barrier to the development of evidence-based dental phobia prevention efforts. Methods Healthy volunteers between the ages of 6 and 35 years will be enrolled across two sites. Participants will complete a conditioning task in a novel virtual reality environment, allowing for control over pre-exposure and the examination of behaviour. A dental startle (a brief, pressurized puff of air to a tooth) will serve as the unconditioned stimulus. Using a within-subjects experimental design, participants will experience a pre-exposed to-be conditioned stimulus, a non-pre-exposed to-be conditioned stimulus, and a neutral control stimulus. Two hypothesized mechanisms, changes in prediction errors and attention, are expected to mediate the association between stimulus condition and fear acquisition, recall, and retention. To ascertain the involvement of pain sensitivity, this construct will be measured through self-report and the cold pressor task. Discussion Dental phobia negatively affects the dental health and overall health of individuals. This study aims to determine the mechanisms through which pre-exposure retards conditioned dental fear acquisition, recall, and retention. A randomized control trial will be used to identify these mechanisms so that they can be precisely targeted and maximally engaged in preventative efforts.

Abstract Aims ARIADNE aimed to assess the association between effects of sacubitril/valsartan and no sacubitril/valsartan treatment and clinical characteristics, functional capacity, and clinical outcomes (cause‐specific mortality and hospitalizations) in outpatients with heart failure (HF) with reduced ejection fraction (HFrEF). Methods ARIADNE was a prospective European registry of 9069 patients with HFrEF treated by office‐based cardiologists or selected primary care physicians. Of the 8787 eligible for analysis, 4173 patients were on conventional HF treatment (non‐S/V group), whereas 4614 patients were either on sacubitril/valsartan treatment at enrolment or started sacubitril/valsartan within 1 month of enrolment (S/V group). We also generated a restricted analysis set (rS/V) including only those 2108 patients who started sacubitril/valsartan treatment within the month prior to or after enrolment. Results At the baseline, average age of patients enrolled in the study was 68 years, and 23.9% (2099/8787) were female. At the baseline, the proportions of patients with New York Heart Association (NYHA) Class III symptoms were 30.9 (1288/4173), 42.8 (1974/4614), and 48.2% (1015/2108), in non‐S/V, S/V, and rS/V groups, respectively. After 12 months of treatment, the proportion of patients with NYHA Class III at baseline who improved to Class II was 32.0% (290/907) in the non‐S/V group vs. 46.3% (648/1399) in S/V group and 48.7% (349/717) in rS/V group. The overall mortality rate was 5.0 per 100 patient‐years. Rates of HF hospitalizations were high (20.9, 20.3, and 21.2 per 100 patient‐years in the non‐S/V, S/V, and rS/V groups, respectively). Emergency room visits without hospitalization occurred in 3.9, 3.2, and 3.9% of patients in the non‐S/V, S/V, and rS/V groups, respectively. Conclusions This large HFrEF European registry provides a contemporary outcome profile of outpatients with HFrEF treated with or without sacubitril/valsartan. In a real‐world setting, sacubitril/valsartan was associated with an improvement of symptoms in patients with HFrEF compared with the conventional HFrEF treatment.

Abstract Aims In people at risk of heart failure (HF) enrolled in the Heart ‘OMics’ in AGEing (HOMAGE) trial, spironolactone reduced circulating markers of collagen synthesis, natriuretic peptides, and blood pressure and improved cardiac structure and function. In the present report, we explored factors associated with dyskalaemia. Methods and results The HOMAGE trial was an open‐label study comparing spironolactone (up to 50 mg/day) versus standard care in people at risk for HF. After randomization, serum potassium was assessed at 1 and 9 months and was defined as low when ≤3.5 mmol/L (hypokalaemia) and high when ≥5.5 mmol/L (hyperkalaemia). Multivariable logistic regression models were constructed to identify clinical predictors of dyskalaemia. A total of 513 participants (median age 74 years, 75% men, median estimated glomerular filtration rate 71 mL/min/1.73 m2) had serum potassium available and were included in this analysis. At randomization, 88 had potassium 5.0 mmol/L. During follow‐up, on at least one occasion, a serum potassium 5.0 mmol/L was observed in 38 (8%) and >5.5 mmol/L in 5 (1.0%) participants. The median (percentile25−75) increase in serum potassium with spironolactone during the study was 0.23 (0.16; 0.29) mmol/L. Because of the low incidence of dyskalaemia, for regression analysis, hypokalaemia and hyperkalaemia thresholds were set at 5.0 mmol/L, respectively. The occurrence of a serum potassium > 5.0 mmol/L during follow‐up was positively associated with the presence of diabetes mellitus {odds ratio [OR]: 1.21 [95% confidence interval (CI) 2.14; 3.79]} and randomization to spironolactone (OR: 2.83 [95% CI 1.49; 5.37]). Conversely, the occurrence of a potassium concentration

Abstract Introduction We evaluated the use of rheumatoid arthritis (RA) disease measures in patients with systemic lupus erythematosus (SLE) in a US community-based rheumatology physician network over 5 years. Methods This retrospective, observational cohort study (GSK Study 213818) of patients with SLE utilized electronic medical records (01 January 2010–31 December 2019) from the United Rheumatology Normalized Integrated Community Evidence database. The index was the date of first SLE diagnosis recorded in the database; the observation period was 5 years post-index. RA disease measures evaluated were: Pain Index, Multi-Dimensional Health Assessment Questionnaire (MD-HAQ), Patient Global Assessment (PtGA), Physician Global Assessment (PGA), Swollen Joint Count (SJC), Tender Joint Count (TJC), Routine Assessment of Patient Index Data 3 (RAPID3), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), and Disease Activity Score 28 (DAS-28). The number of patients with measures utilized, the score on each measure, and proportion of patients per disease activity category were assessed. Results Overall, 5990 patients with SLE were included. The most frequently used measures were Pain Index, SJC, TJC, MD-HAQ, PtGA, RAPID3, and PGA (cumulative use over Years 1–5: 23.9–71.3%). For all measures, frequency of use was lowest in Year 1, followed by a general increase from Year 1 to Year 5. Scores remained relatively stable for most measures, and the proportion of patients in remission or with low/moderate disease activity per RAPID3 increased. Conclusion RA disease measure utilization in SLE was generally infrequent but increased over time. Pain Index and MD-HAQ were the most commonly applied cumulatively across 5 years of follow-up. The rationale for the increased use of these measures in SLE over time requires further exploration. In the absence of a clinically applicable SLE-specific measure, the use of RA measures, for example in conjunction with SLE measures, may provide an alternative approach for measuring disease activity, representing an opportunity to improve patient outcomes.

Abstract The associations between clinical phenotypes of coronavirus disease 2019 (COVID-19) and the host inflammatory response during the transition from peak illness to convalescence are not yet well understood. Blood plasma samples were collected from 129 adult SARS-CoV-2 positive inpatient and outpatient participants between April 2020 and January 2021, in a multi-center prospective cohort study at 8 military hospitals across the United States. Plasma inflammatory protein biomarkers were measured in samples from 15 to 28 days post symptom onset. Topological Data Analysis (TDA) was used to identify patterns of inflammation, and associations with peak severity (outpatient, hospitalized, ICU admission or death), Charlson Comorbidity Index (CCI), and body mass index (BMI) were evaluated using logistic regression. The study population (n = 129, 33.3% female, median 41.3 years of age) included 77 outpatient, 31 inpatient, 16 ICU-level, and 5 fatal cases. Three distinct inflammatory biomarker clusters were identified and were associated with significant differences in peak disease severity (p

Abstract Hepatocellular carcinoma (HCC) is an aggressive liver cancer with limited effective treatment options. In this study, we selected TLR agonists imiquimod (IMQ), gardiquimod (GARD), GS-9620 and DSR 6434, and a small molecule checkpoint inhibitor, BMS-202, for characterization of drug loading and release from radiopaque embolic beads (DC Bead LUMI) for potential use in image-guided transarterial embolization (TACE) of HCC. The maximum drug loading capacity and amount of drug released over time were determined by high performance liquid chromatography and compared with the commonly used anthracycline, doxorubicin hydrochloride (Dox). Maximum drug loading was 204.54 ± 3.87, 65.97 ± 1.54, 65.95 ± 6.96, 65.28 ± 3.09, and 148.05 ± 2.24 mg of drug per milliliter of DC Bead LUMI for Dox, GARD, DSR 6434, IMQ, and BMS-202, respectively. Fast loading and subsequent rapid release in saline were observed for IMQ, GARD, and DSR 6434. These drugs could also be partially removed from the beads by repeated washing with de-ionized water suggesting weak interaction with the beads. Aggregation of IMQ was observed in water and saline. GS-9620 partially decomposed in the solubilizing solution, so loading and release were not characterized. Compared to TLR agonists, slower loading and release were observed for Dox and BMS-202. Potential factors influencing drug loading into and release from DC Bead LUMI including steric hinderance, hydrophobicity, drug pKa, and the electrostatic nature of the beads are discussed. The maximum loading capacity of BMS-202 and Dox in DC Bead LUMI exceeded the maximum theoretical loading capacity of the beads expected from ionic interaction alone suggesting additional drug-bead or drug-drug interactions may play a role. Slightly more release was observed for BMS-202 at early time points followed by a slower release compared to Dox. Further study of these drug-bead combinations is warranted in search of new tools for locoregional delivery of immune-modulating agents for treatment of HCC via drug-eluting bead chemoembolization.

Abstract Background Elevated or reduced responses to sensory stimuli, known as sensory features, are common in autistic individuals and often impact quality of life. Little is known about the neurobiological basis of sensory features in autistic children. However, the brainstem may offer critical insights as it has been associated with both basic sensory processing and core features of autism. Methods Diffusion-weighted imaging (DWI) and parent-report of sensory features were acquired from 133 children (61 autistic children with and 72 non-autistic children, 6–11 years-old). Leveraging novel DWI processing techniques, we investigated the relationship between sensory features and white matter microstructure properties (free-water-elimination-corrected fractional anisotropy [FA] and mean diffusivity [MD]) in precisely delineated brainstem white matter tracts. Follow-up analyses assessed relationships between microstructure and sensory response patterns/modalities and analyzed whole brain white matter using voxel-based analysis. Results Results revealed distinct relationships between brainstem microstructure and sensory features in autistic children compared to non-autistic children. In autistic children, more prominent sensory features were generally associated with lower MD. Further, in autistic children, sensory hyporesponsiveness and tactile responsivity were strongly associated with white matter microstructure in nearly all brainstem tracts. Follow-up voxel-based analyses confirmed that these relationships were more prominent in the brainstem/cerebellum, with additional sensory-brain findings in the autistic group in the white matter of the primary motor and somatosensory cortices, the occipital lobe, the inferior parietal lobe, and the thalamic projections. Limitations All participants communicated via spoken language and acclimated to the sensory environment of an MRI session, which should be considered when assessing the generalizability of this work to the whole of the autism spectrum. Conclusions These findings suggest unique brainstem white matter contributions to sensory features in autistic children compared to non-autistic children. The brainstem correlates of sensory features underscore the potential reflex-like nature of behavioral responses to sensory stimuli in autism and have implications for how we conceptualize and address sensory features in autistic populations.

Abstract Evidence‐based enhanced recovery after surgery (ERAS) programs aim to improve patient outcomes and shorten hospital stays. The objective of this study is to describe the development, implementation, and evolution of an ERAS protocol to optimize the perioperative management for patients undergoing endoscopic skull base surgery for pituitary tumors. A systematic review of the literature was performed, best practices were discussed with stakeholders, and institutional guidelines were established and implemented. Key performance indicators (KPI) were measured and patient‐reported outcome surveys were collected. The ERAS protocol was introduced successfully at our institution. We describe the process of initiation of the program and the perioperative management of our patients. We demonstrated the feasibility of integration of ERAS protocols for pituitary tumors with multidisciplinary engagement, with a particular emphasis on the use of data informatics and metrics to monitor outcomes. We expect that this approach will translate to improved quality of care for these often‐complex patients.

Abstract Recent increases of animal mass mortality events have coincided with substantial changes in global climate. Yet, tractable approaches that predict how climate change will accentuate occurrences of these ecological catastrophes remain nascent. We compiled one of the most comprehensive datasets of lentic fish mortality events, thermal tolerances of affected families, and 1.2 million air and water temperature profiles across 8891 north temperate lakes in North America. Temperature extremes within and across lakes were strongly associated with the three most frequent cause types (infectious agents, summerkills, winterkills). Thermal tolerances mediated the lethality of direct thermal stress, but mortalities of warm‐ and cold‐water fishes occurred at similar temperature deviations. Water and air temperature‐based models accurately predicted contemporary summerkills and suggested ~ 6‐ to 34‐fold increases, respectively, in their frequency by 2100. These models forecast and contextualize impending ecosystem changes in an increasingly volatile world.

Abstract Wastewater-based epidemiology (WBE) has emerged as a valuable epidemiologic tool to detect the presence of pathogens and track disease trends within a community. WBE overcomes some limitations of traditional clinical disease surveillance as it uses pooled samples from the entire community, irrespective of health-seeking behaviors and symptomatic status of infected individuals. WBE has the potential to estimate the number of infections within a community by using a mass balance equation, however, it has yet to be assessed for accuracy. We hypothesized that the mass balance equation-based approach using measured SARS-CoV-2 wastewater concentrations can generate accurate prevalence estimates of COVID-19 within a community. This study encompassed wastewater sampling over a 53-week period during the COVID-19 pandemic in Gainesville, Florida, to assess the ability of the mass balance equation to generate accurate COVID-19 prevalence estimates. The SARS-CoV-2 wastewater concentration showed a significant linear association (Parameter estimate = 39.43, P value

Abstract High bandwidth, low voltage electro-optic modulators with high optical power handling capability are important for improving the performance of analog optical communications and RF photonic links. Here we designed and fabricated a thin-film lithium niobate (LN) Mach-Zehnder modulator (MZM) which can handle high optical power of 110 mW, while having 3-dB bandwidth greater than 110 GHz at 1550 nm. The design does not require etching of thin-film LN, and uses hybrid optical modes formed by bonding LN to planarized silicon photonic waveguide circuits. A high optical power handling capability in the MZM was achieved by carefully tapering the underlying Si waveguide to reduce the impact of optically-generated carriers, while retaining a high modulation efficiency. The MZM has a $$V_\pi L$$ V π L product of 3.1 V.cm and an on-chip optical insertion loss of 1.8 dB.