Search

Background: Dolutegravir (DTG) is part of a first-line antiretroviral therapy (ART) for HIV management in drug-naïve individuals and is recommended for the treatment of HIV during pregnancy. Robust analytical tools to quantify DTG are necessary to support clinical trials that characterize its multi-compartment drug distribution. Methods: Potassium EDTA (K2EDTA) plasma or whole breast milk was spiked with DTG and an isotopically labeled internal standard. Samples were prepared via protein precipitation prior to LC–MS/MS analysis. The assays were validated in accordance with regulatory recommendations. Results: Analytical measuring ranges for DTG quantitation in plasma and breast milk were 100–10,000 ng/mL and 0.500 to 1000 ng/mL, respectively. Inter-assay precision and accuracy were 2.73 % to 3.41 % and −10.6 % to −5.37 % for plasma, and 4.24 % to 12.4 % and −5.63 % to 7.49 % for breast milk, respectively. DTG was stable for three freeze–thaw cycles and for at least 72 h at room temperature in matrix (plasma or breast milk). Additionally, whole blood was stable for 24 h at room temperature and 2 h under conditions of extended heat and humidity. Matrix effects for DTG in plasma and breast milk ranged from 101 % to 108 % and 78.2 % to 99.3 %, respectively. Quantitation in remnant plasma samples yielded measurable concentrations within the primary linearity of the assay. Conclusions: Methods to quantify DTG in human plasma and breast milk have been developed and validated. These assays were designed to satisfy all criteria for implementation in clinical and clinical trial settings.

Abstract Background In Africa, dispensing oral HIV pre-exposure prophylaxis (PrEP) within already strained public health facilities has led to prolonged waiting periods and suboptimal experiences for clients. We sought to explore the acceptability of dispensing PrEP semiannually with interim HIV self-testing (HIVST) versus quarterly PrEP dispensing with clinic-based HIV testing to optimize clinic-delivered PrEP services. Methods We conducted a qualitative study within a non-inferiority individual-level randomized controlled trial testing the effect of six-monthly PrEP dispensing with HIVST compared to the standard-of-care three-monthly PrEP dispensing on PrEP clinical outcomes in Kenya (ClinicalTrials.gov: NCT03593629). Eligible participants were ≥ 18 years, refilling PrEP for the first time, and either in an HIV serodifferent relationship (men and women) or singly enrolled (women only). A subset of participants in the intervention group completed serial in-depth interviews (IDIs) at enrollment, six months, and 12 months. We utilized stratified purposive sampling to ensure representation across participant groups. We analyzed our qualitative data thematically using a combination of inductive and deductive approaches, the latter guided by the Theoretical Framework of Acceptability (TFA). Results Between May 2018 and June 2021, we conducted 120 serial IDIs with 55 participants; 64% (35/55) were in a serodifferent relationship, 64% (35/55) were women, and the median age was 32 years (IQR 27–40). Overall, participants found this novel PrEP delivery model highly acceptable; it was well-liked, private (TFA construct: affective attitude), and less burdensome (TFA construct: burden) compared to standard PrEP delivery. Additionally, participants were confident in their ability to participate in the intervention (TFA construct: self-efficacy). Some participants, however, highlighted model disadvantages, including fewer opportunities for in-person counseling and potentially less accurate HIV testing (TFA construct: opportunity costs). Ultimately, most participants reported that the intervention allowed them to achieve their HIV prevention goals (TFA construct: perceived effectiveness) and that their confidence in at-home HIVST and PrEP continuation increased following each semiannual clinic visit. Conclusions Semiannual PrEP clinic visits supported with six-monthly drug dispensing and interim HIVST was acceptable among PrEP users who experienced the intervention in Kenya. More comprehensive pre-intervention counseling and training on HIVST may help alleviate the client concerns presented, which were often resolved over time with intervention experience.

Abstract Background Adoptive cell cancer therapies aim to re-engineer a patient’s immune cells to mount an anti-cancer response. Chimeric antigen receptor T and natural killer cells have been engineered and proved successful in treating some cancers; however, the genetic methods for engineering are laborious, expensive, and inefficient and can cause severe toxicities when they over-proliferate. Results We examined whether the cell-killing capacity of activated T and NK cells could be targeted to cancer cells by anchoring antibodies to their cell surface. Using metabolic glycoengineering to introduce azide moieties to the cellular surface, we covalently attached a dibenzocyclooctyne-modified antibody using the strain-promoted alkyne azide cycloaddition reaction, creating antibody-conjugated T and NK cells. We targeted the immune cells to tumors possessing the xenoantigen, N-glycolyl neuraminic acid GM3 ganglioside, using the 14F7hT antibody. These activated T and NK cells are “armed” with tumour-homing capabilities that specifically lyses antigen-positive cancer cells without off-target toxicities. Moreover, when exposed to target cells, 14F7hT-conjugated T cells that are not preactivated exhibit increased perforin, granzyme, CD69, and CD25 expression and specific cell killing. Conclusions This research shows the potential for a non-genetic method for redirecting cytotoxic immune cells as a feasible and effective approach for tumor-targeted cell immunotherapy. Graphical Abstract

Abstract Understanding the atomistic structure of the active site during catalytic reactions is of paramount importance in both fundamental studies and practical applications, but such studies are challenging due to the complexity of heterogeneous systems. Here, we use Pt/CeO2 as an example to study the dynamic nature of active sites during the water-gas-shift reaction (WGSR) by combining multiple in situ characterization tools. We show that the different concentrations of interfacial Ptδ+ – O – Ce4+ moieties at Pt/CeO2 interfaces are responsible for the rank of catalytic performance of Pt/CeO2 catalysts: Pt/CeO2-rod > Pt/CeO2-cube > Pt/CeO2-oct. For all the catalysts, metallic Pt is formed during the WGSR, leading to the transformation of the active sites to Pt0 – Ov – Ce3+ and interface reconstruction. These findings shed light on the nature of the active site for the WGSR on Pt/CeO2 and highlight the importance of combining complementary in situ techniques for establishing structure-performance relationships.

Abstract This meta-analysis of 160 semiconductor crystals that were grown in microgravity on orbital vehicles between 1973 and 2016 is based on publicly available information documented in the literature. This analysis provides comparisons of crystal metrics including size, structure quality, uniformity, and improved performance between crystals grown in microgravity or terrestrially. Improvement in at least one of these metrics was observed for 86% of those materials that included data in their studies.

Abstract. Systematic reviews suggest that stand-alone hypnotic suggestions may improve pain outcomes compared with no treatment, waitlist, or usual care. However, in clinical practice, hypnosis is often provided adjunctively with other interventions, which might have different effects than those reported in previous reviews. This systematic review aimed to summarize the analgesic effects of adjunctive hypnosis in adults with clinical pain. Seven databases (MEDLINE, Embase, PsycINFO, Emcare, SCOPUS, CENTRAL, Cochrane) were searched up to January 2024. Randomised controlled trials comparing the analgesic effects of adjunctive hypnosis (hypnosis + primary intervention) with those of the primary intervention alone were included. Meta-analyses (random-effects model) calculated mean differences (MD, [95% confidence intervals]) for pain intensity (0–100). Seventy studies were pooled in meta-analyses (n = 6078). Hypnosis adjunctive to usual care had a small additional analgesic effect (chronic pain: −8.2 [−11.8, −1.9]; medical procedures/surgical pain: −6.9 [−10.4, −3.3]; burn wound care: −8.8 [−13.8, −3.9]). Hypnosis adjunctive to education had a medium additional analgesic effect for chronic pain (−11.5 [−19.7, 3.3]) but not postsurgery pain (−2.0 [−7.8, 3.7]). When paired with psychological interventions, hypnosis slightly increased analgesia in chronic pain only at the three-month follow-up (−2 [−3.7, −0.3]). Hypnosis adjunctive to medicines had a medium additional analgesic effect for chronic pain (−13.2, [−22.5, −3.8]). The overall evidence certainty is very low; therefore, there is still uncertainty about the analgesic effects of adjunctive hypnosis. However, hypnosis adjunct to education may reduce pain intensity for chronic pain. Clarification of proposed therapeutic targets of adjunctive hypnosis to evaluate underlying mechanisms is warranted.

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells’ susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with – or caused by – ferroptosis.

Abstract Intracranial aneurysms (IAs) are present in 2–6% of the global population and can be catastrophic upon rupture with a mortality rate of 30–50%. IAs are commonly detected through time-of-flight magnetic resonance angiography (TOF-MRA), however, this data is rarely available for research and training purposes. The provision of imaging resources such as TOF-MRA images is imperative to develop new strategies for IA detection, rupture prediction, and surgical training. To support efforts in addressing data availability bottlenecks, we provide an open-access TOF-MRA dataset comprising 63 patients, of which 24 underwent interval surveillance imaging by TOF-MRA. Patient scans were evaluated by a neuroradiologist, providing aneurysm and vessel segmentations, clinical annotations, 3D models, in addition to 3D Slicer software environments containing all this data for each patient. This dataset is the first to provide interval surveillance imaging for supporting the understanding of IA growth and stability. This dataset will support computational and experimental research into IA dynamics and assist surgical and radiology training in IA treatment.

Abstract Background Vertebral infections, including vertebral osteomyelitis, septic physitis, and discospondylitis, are rarely reported in goats, and when reported, have been largely limited to necropsy case reports. Objective Describe clinical findings and outcome in goats with vertebral infections evaluated by computed tomography (CT). Animals Five goats with vertebral osteomyelitis, septic physitis, and discospondylitis evaluated by CT. Methods Retrospective case series. Results The most common presenting complaints were progressive weakness, paresis and recumbency. Three goats were tetraparetic and 2 goats had pelvic limb paraparesis. Clinicopathologic findings included leukocytosis, mature neutrophilia, and hyperfibrinogenemia. The most common vertebrae affected were C7‐T1. All 5 goats had discospondylitis with or without vertebral osteomyelitis and septic physitis. Computed tomographic evidence of spinal cord compression was present in 4/5 goats. Medical management (antimicrobials, physical therapy, analgesia, supportive care) was attempted in 4 goats, and 1 goat was euthanized at the time of diagnosis. All 4 goats that were treated regained ambulatory ability and survived to hospital discharge. Conclusions and Clinical Importance Despite severity of CT imaging findings, goats with discospondylitis, septic physitis, and vertebral osteomyelitis can successfully return to ambulatory function. Additional studies are required to determine ideal treatment regimens.

Introduction: The ribonuclease (RNase) A superfamily encodes cationic antimicrobial proteins with potent microbicidal activity toward uropathogenic bacteria. Ribonuclease 6 (RNase6) is an evolutionarily conserved, leukocyte-derived antimicrobial peptide with potent microbicidal activity toward uropathogenic Escherichia coli (UPEC), the most common cause of bacterial urinary tract infections (UTIs). In this study, we generated Rnase6-deficient mice to investigate the hypothesis that endogenous RNase 6 limits host susceptibility to UTI. Methods: We generated a Rnase6EGFP knock-in allele to identify cellular sources of Rnase6 and determine the consequences of homozygous Rnase6 deletion on antimicrobial activity and UTI susceptibility. Results: We identified monocytes and macrophages as the primary cellular sources of Rnase6 in bladders and kidneys of Rnase6EGFP/+ mice. Rnase6 deficiency (i.e., Rnase6EGFP/EGFP) resulted in increased upper urinary tract UPEC burden during experimental UTI, compared to Rnase6+/+ controls. UPEC displayed increased intracellular survival in Rnase6-deficient macrophages. Conclusion: Our findings establish that RNase6 prevents pyelonephritis by promoting intracellular UPEC killing in monocytes and macrophages and reinforce the overarching contributions of endogenous antimicrobial RNase A proteins to host UTI defense.

Eelgrass (Zostera marina) loss occurs worldwide due to increasing water temperatures and decreasing water quality. In the U.S., widgeongrass (Ruppia maritima), a more heat-tolerant seagrass species, is replacing eelgrass in certain areas. Seagrasses enhance sediment denitrification, which helps to mitigate excess nitrogen in coastal systems. Widgeongrass and eelgrass have different characteristics, which may affect sediment nitrogen cycling. We compared net N2 fluxes from vegetated areas (eelgrass and widgeongrass beds, using intact cores that included sediment and plants) and adjacent unvegetated areas from the York River, in the lower Chesapeake Bay during the spring and summer of one year. We found that seagrass biomass, sediment organic matter, and NH4+ fluxes were significantly higher in eelgrass beds than in widgeongrass beds. Eelgrass was also net denitrifying during both seasons, while widgeongrass was only net denitrifying in the summer. Despite differences in the spring, the seagrass beds had a similar rate of N2 production in the summer and both had higher denitrification rates than unvegetated sediments. Both species are important ecosystem components that can help to mitigate eutrophication in coastal areas. However, as the relative composition of these species continues to change, differences in sediment nitrogen cycling may affect regional denitrification capacity.

Abstract Photosynthesis fuels primary production at the base of marine food webs. Yet, in many surface ocean ecosystems, diel-driven primary production is tightly coupled to daily loss. This tight coupling raises the question: which top-down drivers predominate in maintaining persistently stable picocyanobacterial populations over longer time scales? Motivated by high-frequency surface water measurements taken in the North Pacific Subtropical Gyre (NPSG), we developed multitrophic models to investigate bottom-up and top-down mechanisms underlying the balanced control of Prochlorococcus populations. We find that incorporating photosynthetic growth with viral- and predator-induced mortality is sufficient to recapitulate daily oscillations of Prochlorococcus abundances with baseline community abundances. In doing so, we infer that grazers in this environment function as the predominant top-down factor despite high standing viral particle densities. The model-data fits also reveal the ecological relevance of light-dependent viral traits and non-canonical factors to cellular loss. Finally, we leverage sensitivity analyses to demonstrate how variation in life history traits across distinct oceanic contexts, including variation in viral adsorption and grazer clearance rates, can transform the quantitative and even qualitative importance of top-down controls in shaping Prochlorococcus population dynamics.

Caribbean and tropical western Atlantic reefs have declined drastically since the 1970s. In some locales like the Florida Keys, the decline of branching corals approached 98%. These declines are widely attributed to recurring stressors such as high ocean temperatures and disease. The preservation and restoration of reefs is imperative as coral reefs support 25% of the world's known marine species and create billions of dollars in economic value. However, current restoration efforts have low success rates, so researchers are looking to better understand how stony corals respond to and overcome these stressors. Pioneering efforts to elucidate the role of the coral microbiome have shown that microbes are an important component for stony coral health, nutrition, and disease defense. This publication is for various natural resource professionals who want information on corals, microbiomes, and how coral microbial ecology research is pushing our knowledge of corals and restoration forward.

Matrix selection and application is a crucial step in obtaining meaningful results with matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI). Most instruments have a large spatial, and data with adequate spatial resolution can frequently be obtained on a benchtop instrument. The matrix application workflow has been optimized for the imaging of the earthworm (Eisenia hortensis), after exposure to various statins, a class of blood lipid-lowering agents. Lipids are nonpolar, often neutral molecules, making them difficult to ionize, and heightening the need for matrix optimization. The matrices 2,5-dihydroxybenzoic acid (DHB), α-cyano-4-hydroxycinammic acid (CHCA), 1,5-diaminonaphthalene (DAN), and 3,5-dimethoxy-4-hydroxycinnamic acid (sinapinic acid; SA) were studied. Samples were also washed in the ammonium salts of acetate, bicarbonate, formate, sulfate, or water as a control to enhance ionization and improve spatial resolution. A successful matrix for MSI is one that demonstrates homogenous tissue coverage, ionization of the analytes of interest, and does not require excessive laser power for ionization. All matrices showed sufficient tissue coverage; however, CHCA yielded unambiguous images of cholesterol and yielded sufficient signal over the lipid mass range (400–1,000 m/z), indicating that it successfully ionized endogenous lipids. Following additional optimization, the application of 50 mL of 10 mg/mL CHCA following a 5 s salt ammonium sulfate salt wash proved most successful for improving lipid ionization and enhancing spatial resolution.

Historically, 23 freshwater mussel species have been documented from the Buffalo National River (BNR), a 246 km, free-flowing river in northern Arkansas. The potential threats to BNR include land use/land cover changes, eutrophication, recreation, physical habitat changes, and various climate change-related effects. Twelve quantitative mussel bed sites were established and then sampled using a stratified random sampling protocol to evaluate the long-term changes between 2006 and 2020–2021 in population and assemblage characteristics. We compared (1) overall mussel bed persistence, sampling confidence levels and study-wide relative abundances, and compared species’ size and size-frequency distributions; (2) 10 overall site assemblage variables using paired t-tests; (3) site-level mean density, richness, and diversity indices using pair-wise Mann–Whitney U statistics; and (4) assemblage composition using Non-Metric Multidimensional Scaling. The major findings included the following: (1) sampling efforts based on a targeted 80% confidence level appears relatively robust, (2) BNR mussel assemblage composition and structure were relatively stable (however, small mussel bed persistence is a concern), (3) 7 of 23 sites were outliers based on freshwater mussel composition and habitat characteristics, and (4) assemblage composition changed with three species declining (Actinonaias ligamentina, Lasmigona costata, and Ptychobranchus occidentalis) and four species increasing (Cambarunio hesperus, Cyclonaias tuberculata, Eurynia dilatata, and Venustaconcha pleasii) between monitoring events.

Seagrasses provide valuable ecosystem services, including improved water quality, carbon sequestration, and sediment stabilization. Unfortunately, these critical habitats are declining globally due to a range of anthropogenic impacts. Restoration practitioners have made efforts to mitigate loss through the introduction of seagrass transplants. However, seagrass restoration has low success rates and is plagued by water quality concerns and ecosystem degradation. Studies to improve seagrass restoration efforts have targeted different functional taxa to allow for greater stability and recovery of threatened ecosystems, and excluded macro-grazers to limit losses to newly established and restored seagrasses. We hypothesized greater seagrass (Halodule wrightii) health when restored in conjunction with hard clams (Mercenaria mercenaria) and protected from grazers using herbivore exclusion devices (HEDs) in the Indian River Lagoon (IRL), Florida. While our study experienced high rates of seagrass mortality, we were able to observe significant differences in seagrass health between IRL sub-lagoons and observed the positive effects of HEDs on seagrass health. The observed high species mortality highlights how restoration in the IRL is hindered by biotic and abiotic stressors, site selection, and a lack of clear restoration protocols. As we see ongoing declines in water quality and loss of foundational species, informed site selection, greater understanding of grazer presence, and multi-species restoration will provide an informed approach for future seagrass restoration projects globally.

Western Monarch butterflies (Danaus plexippus) migrate from inland breeding ranges to coastal overwintering grounds in California. Given that migratory individuals may make multi-scale habitat selection decisions, we considered a multi-scale species distribution model (SDM) using range-wide climatic and local landscape-level predictors of migratory and overwintering habitat and community-science presence data. The range-wide model output was included as a predictor in the local-scale model, generating multi-scale habitat suitability. The top range-wide predictor was the minimum temperature in December, contributing 83.7% to the model, and was positively associated with presence. At the local scale, the strongest predictors of presence were the range-wide output and percent coverage of low and medium levels of development, contributing > 95%, with 61–63% from the range-wide output, with local-scale suitability coinciding with the California coastal zones. Development’s positive association with overwintering monarch presence was counterintuitive. It is likely that our local-scale model is overfit to these development zones, but it is unclear whether this overfitting resulted from modeler choices, monarchs overwintering close to human development, biased detection near human development, or a combination of these factors. Therefore, alternative approaches to collecting local-scale attribute data are suggested while recognizing the primacy of climate in restricting overwinter sites.

Living shorelines are an increasingly popular way to protect and stabilize waterfronts for coastal property owners. Living shorelines provide valuable benefits to humans, including water quality improvement, habitat, fisheries, and carbon sequestration. Estimating the economic value of the ecosystem services living shorelines offer is an integral part of management decisions. The living shoreline valuation tool can help quantify the costs and benefits of living shorelines projects. This publication briefly describes the ecosystem services associated with living shorelines. The purpose of this publication is to introduce the ecosystem service valuation tool. Our target audience for the living shoreline evaluation tool includes natural resource extension agents, community organizations, and coastal homeowners who want to calculate the value of ecosystem services provided by coastal restoration projects, including living shorelines.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes a spectrum of clinical outcomes that may be complicated by severe asthma. Antiviral immunity is often compromised in patients with asthma; however, whether this is true for SARS-CoV-2 immunity and children is unknown. Objective: We aimed to evaluate SARS-CoV-2 immunity in children with asthma on the basis of infection or vaccination history and compared to respiratory syncytial viral or allergen (eg, cockroach, dust mite)-specific immunity. Methods: Fifty-three children from an urban asthma study were evaluated for medical history, lung function, and virus- or allergen-specific immunity using antibody or T-cell assays. Results: Polyclonal antibody responses to spike were observed in most children from infection and/or vaccination history. Children with atopic asthma or high allergen-specific IgE, particularly to dust mites, exhibited reduced seroconversion, antibody magnitude, and SARS-CoV-2 virus neutralization after SARS-CoV-2 infection or vaccination. TH1 responses to SARS-CoV-2 and respiratory syncytial virus correlated with antigen-respective IgG. Cockroach-specific T-cell activation as well as IL-17A and IL-21 cytokines negatively correlated with SARS-CoV-2 antibodies and effector functions, distinct from total and dust mite IgE. Allergen-specific IgE and lack of vaccination were associated with recent health care utilization. Reduced lung function (forced expiratory volume in 1 second ≤ 80%) was independently associated with (SARS-CoV-2) peptide-induced cytokines, including IL-31, whereas poor asthma control was associated with cockroach-specific cytokine responses. Conclusion: Mechanisms underpinning atopic and nonatopic asthma may complicate the development of memory to SARS-CoV-2 infection or vaccination and lead to a higher risk of repeated infection in these children.

Abstract INTRODUCTION Recruitment of sufficient and diverse participants into clinical research for Alzheimer's disease and related dementias remains a formidable challenge. The primary goal of this manuscript is to provide an overview of an approach to diversifying research recruitment and to provide case examples of several methods for achieving greater diversity in clinical research enrollment. METHODS The University of Kansas Alzheimer's Disease Research Center (KU ADRC) developed MyAlliance for Brain Health (MyAlliance), a service‐oriented recruitment model. MyAlliance comprises a Primary Care Provider Network, a Patient and Family Network, and a Community Organization Network, each delivering tailored value to relevant parties while facilitating research referrals. RESULTS We review three methods for encouraging increased diversity in clinical research participation. Initial outcomes reveal an increase in underrepresented participants from 17% to 27% in a research registry. Enrollments into studies supported by the research registry experienced a 51% increase in proportion of participants from underrepresented communities. DISCUSSION MyAlliance shifts power, resources, and knowledge to community advocates, promoting brain health awareness and research participation, and demands substantial financial investment and administrative commitment. MyAlliance offers valuable lessons for building sustainable, community‐centered research recruitment infrastructure, emphasizing the importance of localized engagement and cultural understanding. Highlights MyAlliance led to a significant increase in the representation of underrepresented racial and ethnic groups and individuals from rural areas. The service‐oriented approach facilitated long‐term community engagement and trust‐building, extending partnerships between an academic medical center and community organizations. While effective, MyAlliance required substantial financial investment, with costs including infrastructure development, staff support, partner organization compensation, and promotional activities, underscoring the resource‐intensive nature of inclusive research recruitment efforts.

Abstract Background Extrapleural pneumonectomy (EPP) is a complex surgical procedure involving en‐bloc resection of the parietal and visceral pleura, lung, pericardium, and ipsilateral diaphragm. Small case series of pleural‐based sarcoma of predominantly pediatric patients suggest EPP may be a life‐prolonging surgical option. We aimed to describe the characteristics and outcomes of adults who underwent EPP at a specialized sarcoma center. Methods Clinicopathologic variables, surgical details, and follow‐up information were extracted for patients undergoing EPP for pleural‐based sarcoma between August 2017 and December 2020. Primary outcomes were event‐free survival (EFS) and overall survival (OS) from the date of EPP. Secondary outcomes were disease‐free interval (DFI) prior to EPP, and early and late postoperative complications. Results Eight patients were identified, seven with soft tissue sarcoma and one with bone sarcoma. Patients had either localized disease with a primary thoracic sarcoma, sarcoma recurrent to the thorax, or de novo metastatic disease. All patients underwent resection of their pleural‐based sarcoma by an experienced cardiothoracic surgeon, and some patients had pre or postoperative treatment. The perioperative morbidity was comparable with previously published reports of EPP performed in mesothelioma patients. At median follow‐up of 22.5 months, median EFS was 6.0 months and OS was 20.7 months. Six patients (75%) had disease recurrence; five (62.5%) died of progressive disease. Two patients (25%) had not recurred: one died of a radiation‐related esophageal rupture, and one was alive with no evidence of disease at 37.0 months. Characteristics of those with the longest EFS included low‐grade histology and achieving a metabolic response to preoperative chemotherapy. Conclusions In adults with pleural‐based sarcoma, EPP is rarely curative but appears to be a feasible salvage procedure when performed at specialized centers. Patient selection is critical with strong consideration given to multimodal therapy to optimize patient outcomes. In the absence of a confirmed response to neoadjuvant treatment, long term survival is poor and EPP should not be recommended.

Older Black men are underrepresented in research despite being disproportionately affected by Alzheimer’s disease (AD) and cardiovascular (CV) risk factors related to AD compared with non-Hispanic Whites. Although dietary interventions have shown promise to reduce modifiable CV risk factors related to AD, Black Americans have lower adherence likely due to lack of cultural considerations. Using a noninterventional convergent parallel mixed-methods approach, this study examined the cultural contexts that inform perceptions of dietary interventions among older Midwestern Black men. All participants completed an online demographic and dietary habit survey prior to focus group discussions. Two focus group discussion sessions were conducted with a total of 10 cognitively normal Black men aged 55 years and older. Survey data were analyzed using a frequency analysis and qualitative data were analyzed using a six-step thematic analysis process. Most men indicated having hypertension ( N = 7, 77.8%) and currently not following a dietary eating pattern ( N = 8, 88.9%). Emerging themes identified included (1) knowledge of dementia, (2) perceptions of dietary interventions, (3) barriers impacting participation in dietary interventions, and (4) overcoming barriers to engage Black men in dietary interventions. Findings from this study should inform the design of future dietary interventions for AD prevention to enhance participation among older Black men.

IntroductionWe conducted research in a post-secondary, large-enrollment science literacy course that asks students to apply multidisciplinary scientific evidence when providing an argument about the potential social and ecological consequences of policy solutions to socioscientific issues (SSI).MethodsCoding schemes were developed to describe students’ levels of proficiency in constructing arguments about the nature of SSI systems and were created through inductive coding of student arguments about SSI systems embedded within a structured decision-making process.ResultsThe coding schemes included student practices in 1) providing reasoning about the potential consequences of multiple solutions for an SSI, 2) linking evidence to reasoning, and 3) sources of evidence. In the highest level in the reasoning coding scheme, students used clear and traceable scientific evidence to address an assumption by specifying how (a mechanism) or by how much, an SSI solution might satisfy a desired policy objective.DiscussionThe resulting framework describes how students apply multidisciplinary scientific evidence to support their SSI reasoning, which may aid researchers and educators in exploring how students interpret and integrate scientific evidence in an SSI-context, with the ultimate goal of bolstering students’ ability to reason about evidence outside the classroom.

Summary: Urinary tract infections (UTIs) commonly afflict people with diabetes. To better understand the mechanisms that predispose diabetics to UTIs, we employ diabetic mouse models and altered insulin signaling to show that insulin receptor (IR) shapes UTI defenses. Our findings are validated in human biosamples. We report that diabetic mice have suppressed IR expression and are more susceptible to UTIs caused by uropathogenic Escherichia coli (UPEC). Systemic IR inhibition increases UPEC susceptibility, while IR activation reduces UTIs. Localized IR deletion in bladder urothelium promotes UTI by increasing barrier permeability and suppressing antimicrobial peptides. Mechanistically, IR deletion reduces nuclear factor κB (NF-κB)-dependent programming that co-regulates urothelial tight junction integrity and antimicrobial peptides. Exfoliated urothelial cells or urine samples from diabetic youths show suppressed expression of IR, barrier genes, and antimicrobial peptides. These observations demonstrate that urothelial insulin signaling has a role in UTI prevention and link IR to urothelial barrier maintenance and antimicrobial peptide expression.

Objective: This retrospective analysis examined serious adverse events (SAEs) and deaths in U.S. lifestyle clinical trials aimed at enhancing cognitive health in older adults. Methods: Data was gathered from trials completed between January 1, 2000, and July 19, 2023, via ClinicalTrials.gov's API. Results: Among these trials, 76% did not report results. The remaining studies fell into four intervention categories: Cognitive/Behavioral, Exercise/Movement, Diet/Supplement, and Multi-modal. When considering all trial types collectively, the findings suggest that lifestyle clinical trials are generally safe. There was no significant increase in the relative risk of experiencing an SAE in the intervention group compared to the control group. However, in terms of relative risk of death, an increase of 28% was observed in the intervention compared to the control, which was statistically significant (X2 (1, N = 36), p

Ocean acidification, the lowering of seawater pH due to increased concentrations of carbon dioxide in the atmosphere, is an emerging environmental challenge associated with climate change. This publication is intended for Florida grade eight educators and other environmental educators of middle school students. We designed a lesson plan to reinforce fundamental concepts in acid-base chemistry, including the pH scale, and to introduce students to waterbody acidification, its negative effects on shell-forming organisms, and the potential role of aquatic plant metabolism (i.e., photosynthesis and respiration) in mitigating these effects. The goal of the lesson plan is to encourage students to link water chemistry and biological processes while learning about the challenges and potential solutions to acidification within a local context. This lesson plan will contribute to state learning standards while generating appreciation for the complexity of the natural environment.

Summary: Pinpointing functional, structural, and redox-sensitive cysteines is a central challenge of chemoproteomics. Here, we present a protocol comprising two dual-enrichment cysteine chemoproteomic techniques that enable capture of cysteines (Cys-LoC) and quantification of cysteine oxidation state (Cys-LOx) in a localization-specific manner. We describe steps for utilizing TurboID-mediated protein biotinylation for enrichment of compartment-specific proteins, followed by click-mediated biotinylation and enrichment of cysteine-containing peptides. Thus, changes to compartment-specific cysteine identification and redox state can be assessed in a variety of contexts.For complete details on the use and execution of this protocol, please refer to Yan et al. (2023).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Cognitive impairment is common in persons with spinal cord injury (SCI), impacting their daily functioning and rehabilitation. This study assesses the extent of self-reported cognitive failures in everyday life in persons with SCI and its relationships with objective neurocognitive measures and psychosocial factors, including depressive mood, anxiety, perceived control, and fatigue. The differences between forty-one adults with a chronic SCI and forty-one able-bodied controls were examined. The participants completed the Cognitive Failures Questionnaire (CFQ) to assess cognitive failure and neurocognitive tests assessing attention and executive functions, as well as a psychosocial assessment. The SCI group reported higher cognitive failure rates than the able-bodied group (31.7% versus 19%, p > 0.05). Objective neurocognitive tests did not significantly correlate with the CFQ scores in either group. However, the CFQ scores were positively associated with most psychosocial factors, even after controlling for covariates. The CFQ scores were significantly associated with depressive mood in persons with SCI. These findings highlight the importance of incorporating self-reported cognitive measures into neurocognitive assessments and rehabilitation planning for adults with SCI. Self-reports capture everyday cognitive challenges that objective tests may miss. Additionally, this study highlights the strong connections between cognitive failures and psychosocial issues, particularly mood disorders, emphasizing the need for comprehensive rehabilitation and psychosocial support post-SCI, addressing both cognitive and emotional wellbeing.

Mounting evidence suggests that antimicrobial peptides and proteins (AMPs) belonging to the RNase A superfamily have a critical role in defending the bladder and kidney from bacterial infection. RNase 6 has been identified as a potent, leukocyte-derived AMP, but its impact on urinary tract infection (UTI) in vivo has not been demonstrated. To test the functional role of human RNase 6, we generated RNASE6 transgenic mice and studied their susceptibility to experimental UTI. In addition, we generated bone marrow-derived macrophages to study the impact of RNase 6 on antimicrobial activity within a cellular context. When subjected to experimental UTI, RNASE6 transgenic mice developed reduced uropathogenic Escherichia coli (UPEC) burden, mucosal injury, and inflammation compared to non-transgenic controls. Monocytes and macrophages were the predominant cellular sources of RNase 6 during UTI, and RNASE6 transgenic macrophages were more proficient at intracellular UPEC killing than non-transgenic controls. Altogether, our findings indicate a protective role for human RNase 6 during experimental UTI.

Abstract Background Goats are increasingly popular as both production animals and pets. The frequency of and factors associated with periparturient reproductive complications in goats are largely unreported. Objectives (1) To report the frequency of periparturient reproductive complications in does presented to university veterinary hospitals and (2) to identify factors associated with uterine tears in the study population. Animals A total of 198 periparturient does presented to 9 university veterinary hospitals from October 2021 to June 2022. Methods Multicenter, cross‐sectional study, with data collected from questionnaires completed by attending veterinarians. Logistic regression was used to identify factors associated with diagnosis of uterine tears. Results Ninety‐three (47%) does had at least 1 periparturient reproductive complication. Periparturient complications included retained fetal membranes (n = 38, 26%), vaginal or perineal trauma (n = 33, 19%), uterine tears (n = 32, 18%), metritis (n = 22, 13%), uterine or vaginal hemorrhage (n = 8, 5%), Cesarean section complications (n = 8, 8%), and uterine prolapse (n = 1, 0.5%). A positive interaction effect was found between small breeds (Nigerian Dwarf and Pygmy) and manipulation on the farm by a layperson upon diagnosis of uterine tears (odd ratios [OR], 5.48; 95% confidence interval [CI], 1.41, 21.25; P = .01). Conclusions and Clinical Importance Periparturient reproductive complications were common. Small breed combined with manipulation on the farm by layperson was associated with diagnosis of uterine tears. Clients should be educated that in the event of dystocia, small breed does are at greater risk of uterine tears and prompt veterinary intervention is critical.

Abstract Uranium isotopic signatures in the rock record are utilized as a proxy for past redox conditions on Earth. However, these signatures display significant variability that complicates the interpretation of specific redox conditions. Using the model uranium-reducing bacterium, Shewanella oneidensis MR-1, we show that the abundance of electron donors (e.g., labile organic carbon) controls uranium isotope fractionation, such that high electron fluxes suppress fractionation. Further, by purifying a key uranium-reducing enzyme, MtrC, we show that the magnitude of fractionation is explicitly controlled by the protein redox state. Finally, using a mathematical framework, we demonstrate that these differences in fractionation arise from the propensity for back-reaction throughout the multi-step reduction of hexavalent uranium. To improve interpretations of observed fractionations in natural environments, these findings suggest that a variable intrinsic fractionation factor should be incorporated into models of uranium isotope systematics to account for differences in electron flux caused by organic carbon availability.

Abstract Objective Schistosomiasis remains a chronic disease of global importance, especially in many rural areas of the world where co-infection with Plasmodium falciparum is common. It is critical to decipher the role of single or co-infected disease scenarios on immune system regulation in such individuals and how such co-infections can either ameliorate or complicate immune response and the consequent disease outcome. First, 10 ml of urine samples, collected between 10:00 am and 2:00 pm, was filtered for diagnosis of schistosomiasis, while egg count, indicative of disease severity, was determined by microscopy. Furthermore, genomic DNA samples extracted from dried blood spots collected on filter paper from one hundred and forty-four Schistosoma haematobium-infected school-children was tested for P. falciparum parasite positivity by an allele-specific nested-PCR analysis of merozoite surface protein (msp)-1 and -2 genes and a real-time PCR assay. In addition, among P. falciparum parasite-positive individuals, we carried out a Taqman SNP genotyping assay to extrapolate the effect of host CD14 (-159 C/T; rs2569190) genetic variants on schistosome egg count. Results Of the 144 individuals recruited, P. falciparum parasite positivity with msp-1 gene were 34%, 43% and 55% for MAD20, RO33 and K1 alleles respectively. Of the co-infected individuals, CD14 genetic variants ranged from 18.8% vs 21.5%, 33.3% vs 44.4%, 9.7% vs 11.8% for single versus schistosome co-infection for the wild type (CC), heterozygous (CT) and mutant (TT) variants respectively. Though the mean egg count for co-infected individuals with CD14 wild type (33.7 eggs per 10 ml of urine) and heterozygote variants (37.5 eggs per 10 ml of urine) were lower than that of schistosome infection alone (52.48 and 48.08 eggs/10 ml of urine respectively), it lacked statistical significance (p-value 0.12 and 0.29), possibly reflecting the benefit of the CD14 activation in schistosome plus malaria co-infection and not schistosome infection alone. In addition, the lower mean egg count in co-infected individuals reveal the benefit of downstream Th1 immune response mitigated by CD14 innate activation that is absent in schistosome infection alone.

Photobiomodulation therapy (cold laser or low-level laser therapy) has been evaluated in human and small animal medicine; however, there is a lack of knowledge about the role photobiomodulation therapy could play in reptile rehabilitation and release. This study used a quantifiable unit, Hounsfield units (bone density measurement), in computed tomography (CT) to evaluate if photobiomodulation therapy showed a significant healing difference between groups treated with photobiomodulation and those that were not. This study included 20 eastern box turtles (Terrapene carolina) presented to a rehabilitation center that sustained shell fractures without penetrating the coelom. They all received similar medical treatments, except that the photobiomodulation group received 250 Hz of red light laser for three minutes three times a week for eight weeks. The turtles were evaluated over the course of two months of therapy. Computed tomography scans were performed prior to therapy, at the midpoint of treatment (one month postinjury), and at the end of the study (two months postinjury). The average Hounsfield units of the fractures were evaluated using nonparametric means, the Wilcoxon/Kruskal–Wallis tests (ranked sums), and found that there were no significant differences in shell density between the photobiomodulation and control groups amongst the scans. This study did find that there was a significant difference (p = 0.0455) between the two groups in regard to the width of the fracture between pre- and post-treatment scans. This study found that the photobiomodulation group had a significantly decreased width of the fracture site between pre-treatment and post-treatment measurements, showing that photobiomodulation could be a relatively easy and effective treatment to promote healing of fractured turtle shells.

Abstract TIGIT is an inhibitory receptor expressed on lymphocytes and can inhibit T cells by preventing CD226 co-stimulation through interactions in cis or through competition of shared ligands. Whether TIGIT directly delivers cell-intrinsic inhibitory signals in T cells remains unclear. Here we show, by analysing lymphocytes from matched human tumour and peripheral blood samples, that TIGIT and CD226 co-expression is rare on tumour-infiltrating lymphocytes. Using super-resolution microscopy and other techniques, we demonstrate that ligation with CD155 causes TIGIT to reorganise into dense nanoclusters, which coalesce with T cell receptor (TCR)-rich clusters at immune synapses. Functionally, this reduces cytokine secretion in a manner dependent on TIGIT’s intracellular ITT-like signalling motif. Thus, we provide evidence that TIGIT directly inhibits lymphocyte activation, acting independently of CD226, requiring intracellular signalling that is proximal to the TCR. Within the subset of tumours where TIGIT-expressing cells do not commonly co-express CD226, this will likely be the dominant mechanism of action.

Abstract Introduction Approximately one third of patients with Acute Type A Aortic Dissection (ATAAD) present with pre-operative malperfusion syndromes (MPS). Of these, mesenteric malperfusion represents the greatest risk to patients with respect to increased short-term mortality. In select patients, it may be feasible to offer a staged approach by treating the mesenteric malperfusion first, optimizing the patient in the intensive care setting and then, following with a central aortic repair. The aim of this systematic review is to summarize cohort studies assessing the role of pre-operative interventions for mesenteric malperfusion. Methods An electronic literature search of five databases was performed to identify all relevant studies providing studies examining short-term mortality on patients who underwent either endovascular or open revascularisation of mesenteric ischemia prior to central aortic repair. The primary outcome was all-cause, short-term mortality. Secondary outcomes were comparative mortality between a delayed repair vs. aortic repair first strategy, rates of postoperative laparotomy, bowel resection, and mortality following delayed aortic repair. Results The search strategy identified 8 studies qualifying for inclusion, with a total of 180 patients who underwent delayed aortic surgery in the setting of mesenteric MPS. The weighted short-term mortality following a mesenteric revascularisation first, delayed aortic surgery strategy was 22.5%. This strategy was also associated with a significantly lower mortality than a central repair first strategy (OR 0.07, 95% CI 0.02–0.27), and a significantly lower rate of postoperative laparotomy/bowel resection (OR 0.05, 95% CI 0.02–0.14). If patients survive to receive central repair, the weighted short-term mortality postoperatively is low (2.1%). Conclusion A summary of this evidence reveals a lower short-term mortality in hemodynamically stable patients with mesenteric malperfusion, along with a reduction in postoperative laparotomy/bowel resections. Of those patients who survive to receive central repair, short-term mortality remains very low in the select group of hemodynamically stable patients. Further high-quality studies with randomized or propensity matched data are required to verify these results.

Hand hygiene is central to the prevention of healthcare-associated infection. In low-income settings, barriers to health worker hand hygiene may include inconsistent availability of hand hygiene supplies at the point of care. However, there is a lack of knowledge of interventions to improve and sustain health worker hand hygiene in these settings. This pilot study evaluates acceptability and feasibility of a personally-worn hand hygiene holster device for improving point-of-care access to alcohol-based handrub (ABHR). Holsters were distributed to clinical staff at a hospital in Liberia in July–September 2021. Data collection included 2,066 structured observations of hand hygiene behavior, six spot checks of supply availability, and focus group discussions with 13 clinical staff. The Integrated Behavioral Model for Water, Sanitation, and Hygiene (IBM-WASH) provided a framework for study design and qualitative analysis. Acceptability of the intervention was high, with users reporting that holsters were comfortable, easy to use, and aligned with their professional identities. Feasibility depended on consistent ABHR availability, which may diminish sustainability of this intervention. The hand hygiene holster is a promising tool for improving health worker hand hygiene behavior, but solutions to ABHR supply chain and distribution constraints are necessary to support sustainability of this intervention. HIGHLIGHTS This pilot study evaluated the feasibility and acceptability of a hand hygiene holster device to improve access to point-of-care hand hygiene in Liberian health facilities.; Users reported satisfaction with holsters and many felt that this intervention made hand hygiene more accessible during patient care.; Further research should explore the impact of the holster intervention on health worker hand hygiene behavior.;

BackgroundBubble continuous positive airway pressure (bCPAP) is used in resource-limited settings for children with respiratory distress. Low-cost modifications of bCPAP use 100% oxygen and may cause morbidity from oxygen toxicity. We sought to test a novel constructible low-cost entrainment syringe system (LESS) oxygen blender with low-cost modified bCPAP in a relevant clinical setting.MethodsWe conducted a clinical trial evaluating safety of the LESS O2 blender among hospitalized children under five years old in rural Cambodia evaluating the rate of clinical failure within one hour of initiation of the LESS O2 blender and monitoring for any other blender-related complications.FindingsThirty-two patients were included. The primary outcome (clinical failure) occurred in one patient (3.1%, 95% CI = 0.1–16.2%). Clinical failure was defined as intubation, death, transfer to another hospital, or two of the following: oxygen saturation

Background: Pregnancy is associated with a higher risk of adverse symptoms and outcomes for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection for both mother and neonate. Antibodies can provide protection against SARS-CoV-2 infection and are induced in pregnant women after vaccination or infection. Passive transfer of these antibodies from mother to fetus in utero may provide protection to the neonate against infection. However, it is unclear whether the magnitude or quality and kinetics of maternally derived fetal antibodies differs in the context of maternal infection or vaccination. Objective: We aimed to determine whether antibodies transferred from maternal to fetus differed in quality or quantity between infection- or vaccination-induced humoral immune responses. Methods: We evaluated 93 paired maternal and neonatal umbilical cord blood plasma samples collected between October 2020 and February 2022 from a birth cohort of pregnant women from New Orleans, Louisiana, with histories of SARS-CoV-2 infection and/or vaccination. Plasma was profiled for the levels of spike-specific antibodies and induction of antiviral humoral immune functions, including neutralization and Fc-mediated innate immune effector functions. Responses were compared between 4 groups according to maternal infection and vaccination. Results: We found that SARS-CoV-2 vaccination or infection during pregnancy increased the levels of antiviral antibodies compared to naive subjects. Vaccinated mothers and cord samples had the highest anti-spike antibody levels and antiviral function independent of the time of vaccination during pregnancy. Conclusions: These results show that the most effective passive transfer of functional antibodies against SARS-CoV-2 in utero is achieved through vaccination, highlighting the importance of vaccination in pregnant women.

Objective: Energy-intensive kidney reabsorption processes essential for normal whole-body function are maintained by tubular epithelial cell metabolism. Although tubular metabolism changes markedly following acute kidney injury (AKI), it remains unclear which metabolic alterations are beneficial or detrimental. By analyzing large-scale, publicly available datasets, we observed that AKI consistently leads to downregulation of the mitochondrial pyruvate carrier (MPC). This investigation aimed to understand the contribution of the tubular MPC to kidney function, metabolism, and acute injury severity. Methods: We generated tubular epithelial cell-specific Mpc1 knockout (MPC TubKO) mice and employed renal function tests, in vivo renal 13C-glucose tracing, mechanistic enzyme activity assays, and tests of injury and survival in an established rhabdomyolysis model of AKI. Results: MPC TubKO mice retained normal kidney function, displayed unchanged markers of kidney injury, but exhibited coordinately increased enzyme activities of the pentose phosphate pathway and the glutathione and thioredoxin oxidant defense systems. Following rhabdomyolysis-induced AKI, compared to WT control mice, MPC TubKO mice showed increased glycolysis, decreased kidney injury and oxidative stress markers, and strikingly increased survival. Conclusions: Our findings suggest that decreased renal tubular mitochondrial pyruvate uptake hormetically upregulates oxidant defense systems before AKI and is a beneficial adaptive response after rhabdomyolysis-induced AKI. This raises the possibility of therapeutically modulating the MPC to attenuate AKI severity.

IntroductionSignificant evidence suggests a connection between transplant rejection and the presence of high levels of pre-existing memory T cells. Viral infection can elicit viral-specific memory T cells that cross-react with allo-MHC capable of driving allograft rejection in mice. Despite these advances, and despite their critical role in transplant rejection, a systematic study of allo-reactive memory T cells, their specificities, and the role of cross-reactivity with viral antigens has not been performed.MethodsHere, we established a model to identify, isolate, and characterize cross-reactive T cells using Nur77 reporter mice (C57BL/6 background), which transiently express GFP exclusively upon TCR engagement. We infected Nur77 mice with lymphocytic choriomeningitis virus (LCMV-Armstrong) to generate a robust memory compartment, where quiescent LCMV-specific memory CD8+ T cells could be readily tracked with MHC tetramer staining. Then, we transplanted LCMV immune mice with allogeneic hearts and monitored expression of GFP within MHC-tetramer defined viral-specific T cells as an indicator of their ability to cross-react with alloantigens.ResultsStrikingly, prior LCMV infection significantly increased the kinetics and magnitude of rejection as well as CD8+ T cell recruitment into allogeneic, but not syngeneic, transplanted hearts, relative to non-infected controls. Interestingly, as early as day 1 after allogeneic heart transplant an average of ~8% of MHC-tetramer+ CD8+ T cells expressed GFP, in contrast to syngeneic heart transplants, where the frequency of viral-specific CD8+ T cells that were GFP+ was

The prevalence of suicidal thoughts and behaviors across distinct intersections of race/ethnicity and gender among adolescents remains understudied. The current study seeks to address this important gap in suicide scholarship using a statewide representative sample of U.S. Florida middle school and high school adolescents. Data drawn from the 2022 Florida Youth Substance Abuse Survey (FYSAS) (N = 41,764) were analyzed to examine disparities in suicidal thoughts and suicide attempts among 26 racial/ethnic and gender subgroups of middle school and high school aged adolescents. Survey-weighted prevalence estimates for both suicidality outcomes were generated, and binary contrasts were used to assess the statistical significance of the differences in the probabilities between members of each subgroup and youth belonging to all other subgroups. Our results indicate that the prevalence of suicidal thoughts and attempts was highly gendered and varied according to racial/ethnic subgroups. Native American girls reported more suicidal thoughts (49.9%) and attempts (16.5%) in the past 12 months than any race/gender group. Other racial/ethnic and gender groups that reported particularly high rates of suicidal thoughts and attempts were West Indian/Caribbean female adolescents (48.8% and 13.4%, respectively), Puerto Rican female adolescents (48.5% and 14.7%, respectively), and Black/non-Hispanic female adolescents (19.9% and 15.6%, respectively). Because certain gender and race/ethnic subgroups are at an increased risk for suicidality, more research is needed to better understand the risk and protective factors to determine which suicide prevention strategies might best serve each group.

Abstract Background Type 2 diabetes mellitus (T2DM) and its associated complications puts considerable strain on healthcare systems. With the global incidence of T2DM increasing, effective disease management is essential. Physical activity (PA) is a key component of T2DM management; however, rates of PA engagement are low in this population. Developing effective and sustainable interventions that encourage PA is a high priority. Electrically assisted bicycles are becoming increasingly popular and may increase PA in healthy adults. This study aimed to provide evidence of the feasibility of conducting a randomized controlled trial to evaluate the efficacy of an e-cycling intervention to increase PA and improve health in individuals with T2DM. Methods A parallel-group two-arm randomized, waitlist-controlled pilot study was conducted. Individuals were randomized to either an e-bike intervention or standard care. The intervention incorporated two one-to-one e-bike skills training and behavioural counselling sessions delivered by a community-based cycling charity, followed by a 12-week e-bike loan with two further sessions with the instructors. Feasibility was assessed via measures related to recruitment, retention and intervention implementation. Post-intervention interviews with instructors and participants explored the acceptability of the study procedures and intervention. Clinical, physiological and behavioural outcomes were collected at baseline and post-intervention to evaluate the intervention’s potential. Results Forty participants (M age = 57) were randomized, of which 34 were recruited from primary care practices. Thirty-five participants were retained in the trial. The intervention was conducted with high fidelity (> 80% content delivered). E-bike training provided participants with the skills, knowledge and confidence needed to e-bike independently. Instructors reported being more confident delivering the skills training than behavioural counselling, despite acknowledging its importance. The study procedures were found to be acceptable to participants. Between-group differences in change during the intervention were indicative of the interventions potential for improving glucose control, health-related quality of life and cardiorespiratory fitness. Increases in overall device measured moderate-to-vigorous PA behaviour following the intervention were found, and there was evidence that this population self-selected to e-cycle at a moderate intensity. Conclusions The study’s recruitment, retention, acceptability and potential efficacy support the development of a definitive trial subject to identified refinements. Trial registration ISRCTN, ISRCTN67421464 . Registered 17/12/2018.

Abstract Background The progressive deregulation of the immune system with age, termed immunosenescence, has been well studied in mammalian systems, but studies of immune function in long-lived, wild, non-mammalian populations are scarce. In this study we leverage a 38-year mark-recapture study to quantify the relationships among age, sex, survival, reproductive output and the innate immune system in a long-lived reptile, yellow mud turtles (Kinosternon flavescens; Testudines; Kinosternidae). Methods We estimated rates of survival and age-specific mortality by sex based on mark-recapture data for 1530 adult females and 860 adult males over 38 years of captures. We analyzed bactericidal competence (BC), and two immune responses to foreign red blood cells - natural antibody-mediated haemagglutination (NAbs), and complement-mediated haemolysis ability (Lys) - in 200 adults (102 females; 98 males) that ranged from 7 to 58 years of age captured in May 2018 during their emergence from brumation, and for which reproductive output and long-term mark-recapture data were available. Results We found that females are smaller and live longer than males in this population, but the rate of accelerating mortality across adulthood is the same for both sexes. In contrast, males exhibited higher innate immunity than females for all three immune variables we measured. All immune responses also varied inversely with age, indicating immunosenescence. For females that reproduced in the preceding reproductive season, egg mass (and therefore total clutch mass) increased with age,. In addition to immunosenescence of bactericidal competence, females that produced smaller clutches also had lower bactericidal competence. Conclusions Contrary to the general vertebrate pattern of lower immune responses in males than females (possibly reflecting the suppressive effects of androgens), we found higher levels of all three immune variables in males. In addition, contrary to previous work that found no evidence of immunosenescence in painted turtles or red-eared slider turtles, we found a decrease in bactericidal competence, lysis ability, and natural antibodies with age in yellow mud turtles.

Cell expansion in a discrete region called the elongation zone drives root elongation. Analyzing time lapse images can quantify the expansion in kinematic terms as if it were fluid flow. We used horizontal microscopes to collect images from which custom software extracted the length of the elongation zone, the peak relative elemental growth rate (REGR) within it, the axial position of the REGR peak, and the root elongation rate. Automation enabled these kinematic traits to be measured in 1575 Arabidopsis seedlings representing 162 recombinant inbred lines (RILs) derived from a cross of Cvi and Ler ecotypes. We mapped ten quantitative trait loci (QTL), affecting the four kinematic traits. Three QTL affected two or more traits in these vertically oriented seedlings. We compared this genetic architecture with that previously determined for gravitropism using the same RIL population. The major QTL peaks for the kinematic traits did not overlap with the gravitropism QTL. Furthermore, no single kinematic trait correlated with quantitative descriptors of the gravitropism response curve across this population. In addition to mapping QTL for growth zone traits, this study showed that the size and shape of the elongation zone may vary widely without affecting the differential growth induced by gravity.

Foot-and-mouth disease (FMD) is endemic in many Asian countries, with outbreaks occurring regularly due to viruses from serotypes O, A, and Asia1 that co-circulate in the region. The ability to rapidly characterize new virus occurrences provides critical information to understand the epidemiology and risks associated with field outbreaks, and helps in the selection of appropriate vaccines to control the disease. FMD lineage-specific characterization is usually determined through sequencing; however, this capacity is not always readily available. In this study, we provide a panel of real-time RT-PCR (rRT-PCR) assays to allow differentiation of the FMD virus (FMDV) lineages known to have been co-circulating in Asia during 2020. This panel included five new rRT-PCR assays designed to detect lineages O/ME-SA/PanAsia-PanAsia-2, O/ME-SA/Ind-2001, O/SEA/Mya-98, O/CATHAY, and A/ASIA/Sea-97, along with three published rRT-PCR assays for A/ASIA/Iran-05, A/ASIA/G-VII, and Asia1 serotypes. Samples of known FMD lineage (n = 85) were tested in parallel with all eight lineage-specific assays and an established 3D pan-FMD rRT-PCR assay, and comparative limit of detection (LOD) experiments were conducted for the five newly developed assays. All samples (85/85) were assigned to the correct serotype, and the correct lineage was assigned for 70 out of 85 samples where amplification only occurred with the homologous assay. For 13 out of 85 of the samples, there was amplification in two assays; however, the correct lineage could be designated based on the strongest Ct values for 12 out of 13 samples. An incorrect lineage was assigned for 3 out of 85 samples. The amplification efficiencies for the five new rRT-PCR assays ranged between 79.7 and 100.5%, with nucleic acid dilution experiments demonstrating broadly equivalent limits of detection when compared to the 3D pan-FMD rRT-PCR assay. These new tests, together with other published lineage-specific rRT-PCR assays, constitute a panel of assays (or molecular toolbox) that can be selected for use in FMD endemic countries (individually or a subset of the assays depending on region/lineages known to be circulating) for rapid characterization of the FMDV lineages circulating in Asia at a relatively low cost. This molecular toolbox will enhance the ability of national laboratories in endemic settings to accurately characterize circulating FMDV strains and facilitate prompt implementation of control strategies, and may be particularly useful in settings where it is difficult to access sequencing capability.

Mutations in the CLN5 gene cause the fatal, pediatric, neurodegenerative disease CLN5 neuronal ceroid lipofuscinosis. Affected children suffer progressive neuronal loss, visual failure and premature death. Presently there is no treatment. This study evaluated dual intracerebroventricular (ICV) and intravitreal (IVT) administration of a self-complementary adeno-associated viral vector encoding ovine CLN5 (scAAV9/oCLN5) into CLN5 affected sheep (CLN5−/−) at various disease stages. CLN5 disease progression was slowed in pre-symptomatic sheep who received a moderate dose of scAAV9/oCLN5, whilst a higher ICV dose treatment in early and advanced symptomatic animals delayed or halted disease progression. Intracranial (brain) volume loss was attenuated in all treatment cohorts, and visual function was also sustained in both the early and advanced symptomatic treated sheep over the 24-month duration of the study. Robust CLN5 protein expression was detected throughout the brain and spinal cord, and improvements in central nervous system and retinal disease correlates were observed. These findings hold translational promise for extending and improving the quality of life in both pre-symptomatic and symptomatic CLN5 patients, and prompted the initiation of the first in-human Phase I/II clinical trial testing ICV/IVT administration of scAAV9 encoding human CLN5 (https://clinicaltrials.gov/; NCT05228145).

International and domestic fisheries management bodies are increasingly embracing a management procedure (MP) approach to managing their living marine resources. An added advantage of an MP approach is the opportunity for strategic and impactful engagement and collaboration among resource managers, user groups, civil society and other stakeholder groups in MP development, adoption, and implementation. We consider examples from four regional fisheries bodies (i.e., RFMOs and a multi-lateral body) where stakeholders are contributing to the development of MPs for several stocks to varying degrees. These case studies highlight differing structures and processes for open and transparent stakeholder engagement in management strategy evaluation (MSE) and MP development. We identify that one important difference between sufficient and insufficient stakeholder engagement in these cases is the presence or absence of formalised structures and processes for inclusive and open stakeholder engagement, where there are key roles for stakeholder inputs and feedback during key stages of MSE and MP development. We highlight the benefits of engaging stakeholders from the outset of the MP development process, including designing processes, agreeing on the timelines and workplan for MSE and providing inputs that can lead to the successful adoption of an appropriate MP. We then consider how stakeholder engagement may be improved in other multi-lateral regional fisheries bodies, such as the NEAFC/Northeast Atlantic coastal States management forums, as well as other relevant RFMOs.