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Abstract Multiple respiratory viruses lead to high morbidity and mortality, yet global surveillance platforms focus primarily on seasonal influenza viruses. The COVID-19 pandemic and new RSV vaccines highlight the importance of a broader approach. Upper respiratory tract swabs from children aged 24–59 months presenting with influenza-like illness in The Gambia were collected during follow-up of a live-attenuated influenza vaccine randomised controlled trial in 2017–18. A microfluidic quantitative polymerase chain reaction (qPCR) assay was established and used to detect 21 respiratory viruses. 76.6% of samples had one or more viruses detected (n = 121/158). The viruses detected most frequently were rhinovirus (n = 37/158, 23.4%) and adenovirus (n = 34/158, 21.5%), followed by parainfluenza virus 3, influenza B and human metapneumovirus B. A third of positive samples had multiple viruses detected (two n = 31/121, 25.6%; three n = 9/121, 7.4%). Our data demonstrates how microfluidic qPCR is a useful tool for high-throughput, comprehensive detection of multiple respiratory viruses in surveillance platforms. Rapidly changing epidemiology exemplifies the need for new, broader approaches to virus surveillance in low-resource settings to respond to future epidemics and to guide the need for and use of new prevention and therapeutic measures.

Abstract Vast alteration of the biosphere by humans is causing a sixth mass extinction, driven in part by an increase in infectious diseases. The emergence of the lethal fungal pathogen Batrachochytrium dendrobatidis (Bd) has devastated global amphibian biodiversity. Given the lack of any broadly applicable methods to reverse these impacts, the future of many amphibians appears grim. The Sierra Nevada yellow-legged frog (Rana sierrae) is highly susceptible to Bd infection and most R. sierrae populations are extirpated following disease outbreaks. However, some populations persist and eventually recover, and frogs in these recovering populations have increased resistance against infection. Here, we conduct a 15-year reintroduction study and show that frogs collected from recovering populations and reintroduced to vacant habitats can reestablish populations despite the presence of Bd. In addition, the likelihood of establishment is influenced by site, cohort, and frog attributes. Results from viability modeling suggest that many reintroduced populations have a low probability of extinction over 50 years. These results provide a rare example of how reintroduction of resistant individuals can allow the landscape-scale recovery of disease-impacted species, and have broad implications for amphibians and other taxa that are threatened with extinction by novel pathogens.

Abstract Background HIV treatment programs in Africa have implemented centralized testing for routine viral load monitoring (VLM), which may result in specimen processing delays inhibiting timely return of viral load results. Decentralized, point-of-care (PoC) VLM is a promising tool for expediting HIV clinical decision-making but remains unavailable in most African settings. We qualitatively explored the perceived feasibility and appropriateness of PoC VLM to address gaps along the viral load monitoring continuum in rural Uganda. Methods Between May and September 2022, we conducted 15 in-depth interviews with HIV clinicians (facility in-charges, clinical officers, nurses, counselors) and six focus group discussions with 47 peer health workers from three south-central Ugandan districts. Topics explored centralized VLM implementation and opportunities/challenges to optimizing routine VLM implementation with PoC testing platforms. We explored perspectives on PoC VLM suitability and feasibility using iterative thematic analysis. Applying the Framework Method, we then mapped salient constraints and enablers of PoC VLM to constructs from the Consolidated Framework for Implementation Research. Results Clinicians and peers alike emphasized centralized viral load monitoring’s resource-intensiveness and susceptibility to procedural/infrastructural bottlenecks (e.g., supply stockouts, testing backlogs, community tracing of clients with delayed VLM results), inhibiting timely clinical decision-making. Participants reacted enthusiastically to the prospect of PoC VLM, anticipating accelerated turnarounds in specimen processing, shorter and/or fewer client encounters with treatment services, and streamlined efficiencies in HIV care provision (including expedited VLM-driven clinical decision-making). Anticipated constraints to PoC VLM implementation included human resource requirements for processing large quantities of specimens (especially when machinery require repair), procurement and maintenance costs, training needs in the existing health workforce for operating point-of-care technology, and insufficient space in lower-tier health facilities to accommodate installation of new laboratory equipment. Conclusions Anticipated implementation challenges, primarily clustering around resource requirements, did not diminish enthusiasm for PoC VLM monitoring among rural Ugandan clinicians and peer health workers, who perceived PoC platforms as potential solutions to existing inefficiencies within the centralized VLM ecosystem. Prioritizing PoC VLM rollout in facilities with available resources for optimal implementation (e.g., adequate physical and fiscal infrastructure, capacity to manage high specimen volumes) could help overcome anticipated barriers to decentralizing viral load monitoring.

Abstract Achieving precise and controllable hierarchical self-assembly of functional nanoclusters within crystal lattices to create distinct architectures is of immense significance, yet it creates considerable challenges. Here we successfully synthesized a silver nanowheel Ag40, along with its optically pure enantiomers S-/R-Ag40. Each species possesses an internal nanospace and exhibits host-guest interactions. These structures are constructed from primary building blocks (Ag9). By manipulating the surface anions and guest molecules, the nanowheels function as secondary building blocks, spontaneously organizing into complex double- and triple-helical crystalline superstructures or one-dimensional chains {Ag41} n through conformational matching and diverse noncovalent interactions. Moreover, we demonstrate that the water-mediated complex specifically assembled with uridine monophosphate nucleotides, resulting in chiral assemblies of Ag40 that exhibit chiroptical activity for specific recognition. Our findings provide insights into the efficient construction of assemblies with hollow frameworks and propose strategies for superstructure engineering by manipulating surface motifs.

Abstract Red mud is a by-product from alumina industry. Global production of red mud was around 369 million tons in 2023, and India contributed over 6% of total. Landfilling of red mud may leach out heavy metals to soil and water, which could have negative consequences for the ecosystem. Incorporating the red mud in a geopolymer matrix is a safe option. This paper aims to analyse the environmental impact of the 1.0 m3 red mud containing geopolymer paving blocks using GaBi (Indian extension database) software. The data used for the analysis was generated from the studies conducted in continuous geopolymer pilot plant (10 tons/day). The analysis shows the major contributions from alkali activators and electricity. Red mud paving blocks exhibit global warming potential (275 kg CO2 eq.), human toxicity (51.7 kg DCB eq.), and terrestrial ecotoxicity potential (0.441 kg DCB eq.). Red mud blocks have similar acidification (1.65 kg SO2 eq.) and abiotic depletion potential (fossil) (3080 MJ) on comparison with cement paving blocks. Red mud geopolymer paving blocks offer a sustainable alternative with the reduced environmental footprint compared to conventional methods.

Background: The workload of musculoskeletal radiologists has come under pressure. Our objective was to estimate the reading times of common musculoskeletal MRI examinations. Methods: A total of 144 radiologists were asked to estimate reading times (including interpretation and reporting) for MRI of the shoulder, elbow, wrist, hip, knee, and ankle. Multivariate linear regression analyses were performed. Results: Reported median reading times with interquartile range (IQR) for the shoulder, elbow, wrist, hip, knee, and ankle were 10 (IQR 6–14), 10 (IQR 6–14), 11 (IQR 7.5–14.5), 10 (IQR 6.6–13.4), 8 (IQR 4.6–11.4), and 10 (IQR 6.5–13.5) min, respectively. Radiologists aged 35–44 years reported shorter reading times for the shoulder (β coefficient [β] = B-3.412, p = 0.041), hip (β = −3.596, p = 0.023), and knee (β = −3.541, p = 0.013) than radiologists aged 45–54 years. Radiologists not working in an academic/teaching hospital reported shorter reading times for the hip (β = −3.611, p = 0.025) and knee (β = −3.038, p = 0.035). Female radiologists indicated longer reading times for all joints (β of 2.592 to 5.186, p ≤ 0.034). Radiologists without musculoskeletal fellowship training indicated longer reading times for the shoulder (β = 4.604, p = 0.005), elbow (β = 3.989, p = 0.038), wrist (β = 4.543, p = 0.014), and hip (β = 2.380, p = 0.119). Radiologists with p ≤ 0.045), and radiologists with 5–10 years of post-residency experience reported longer reading time for the knee (β = 3.660, p = 0.045) than those with >10 years of post-residency experience. Conclusions: There is substantial variation among radiologists in reported reading times for common musculoskeletal MRI examinations. Several radiologist-related determinants appear to be associated with reading speed, including age, gender, hospital type, training, and experience.

Abstract Ecosystem services such as pollination and biocontrol may be severely affected by emerging nano/micro-plastics (NMP) pollution. Here, we synthesize the little-known effects of NMP on pollinators and biocontrol agents on the organismal, farm and landscape scale. Ingested NMP trigger organismal changes from gene expression, organ damage to behavior modifications. At the farm and landscape level, NMP will likely amplify synergistic effects with other threats such as pathogens, and may alter floral resource distributions in high NMP concentration areas. Understanding exposure pathways of NMP on pollinators and biocontrol agents is critical to evaluate future risks for agricultural ecosystems and food security.

Abstract Background Inadequate collaboration in healthcare can lead to medical errors, highlighting the importance of interdisciplinary teamwork training. Virtual reality (VR) simulation-based training presents a promising, cost-effective approach. This study evaluates the effectiveness of the Team Emergency Assessment Measure (TEAM) for assessing healthcare student teams in VR environments to improve training methodologies. Methods Forty-two medical and nursing students participated in a VR-based neurological emergency scenario as part of an interprofessional team training program. Their performances were assessed using a modified TEAM tool by two trained coders. Reliability, internal consistency, and concurrent validity of the tool were evaluated using intraclass correlation coefficients (ICC) and Cronbach’s alpha. Results Rater agreement on TEAM’s leadership, teamwork, and task management domains was high, with ICC values between 0.75 and 0.90. Leadership demonstrated strong internal consistency (Cronbach’s alpha = 0.90), while teamwork and task management showed moderate to acceptable consistency (alpha = 0.78 and 0.72, respectively). Overall, the TEAM tool exhibited high internal consistency (alpha = 0.89) and strong concurrent validity with significant correlations to global performance ratings. Conclusion The TEAM tool proved to be a reliable and valid instrument for evaluating team dynamics in VR-based training scenarios. This study highlights VR’s potential in enhancing medical education, especially in remote or distanced learning contexts. It demonstrates a dependable approach for team performance assessment, adding value to VR-based medical training. These findings pave the way for more effective, accessible interdisciplinary team assessments, contributing significantly to the advancement of medical education.

Abstract Background Cervical cancer continues to threaten women’s health, especially in low-resource settings. Regular follow-up after screening and treatment is an effective strategy for monitoring treatment outcomes. Consequently, understanding the factors contributing to patient non-attendance of scheduled follow-up visits is vital to providing high-quality care, reducing morbidity and mortality, and unnecessary healthcare costs in low-resource settings. Methods A descriptive qualitative study was done among healthcare providers and patients who attended the cervical cancer screening clinic at Mbarara Regional Referral Hospital in southwestern Uganda. In-depth interviews were conducted using a semi-structured interview guide. Interviews were audio-recorded, transcribed verbatim, and thematically analysed in line with the social-ecological model to identify barriers and facilitators. Results We conducted 23 in-depth interviews with 5 healthcare providers and 18 patients. Health system barriers included long waiting time at the facility, long turnaround time for laboratory results, congestion and lack of privacy affecting counselling, and healthcare provider training gaps. The most important interpersonal barrier among married women was lacking support from male partners. Individual-level barriers were lack of money for transport, fear of painful procedures, emotional distress, and illiteracy. Inadequate and inaccurate information was a cross-cutting barrier across the individual, interpersonal, and community levels of the socio-ecological model. The facilitators were social support, positive self-perception, and patient counselling. Conclusions Our study revealed barriers to retention in care after cervical cancer screening, including lack of partner support, financial and educational constraints, and inadequate information. It also found facilitators that included social support, positive self-perception, and effective counselling.

Abstract Background UKA is a well-established treatment option for anteromedial osteoarthritis of the knee, resulting in superior functional outcomes but also higher revision rates than TKA. This study aimed to compare the outcomes of UKA, TKA, UKA converted to TKA using identical standard implants and revised TKA to support clinical decision-making. Methods In this study, we retrospectively examined 116 patients who underwent UKA, 77 patients who received TKA, 28 patients whose UKA was converted to TKA using identical standard implants, and 21 patients who had a one-stage revision of TKA. The mean age at operation was 66.5 years (39–90 years), with a mean BMI of 28.8 kg/m2 (17.4–58.8) and a mean follow-up period of four years (0.9–9.9 years). We assessed various PROMs, including Oxford Knee Score, UCLA score, KSS score, and a modified WOMAC-Score as well as patient satisfaction and ability to resume daily activities, work, and sports. Results The highest patient satisfaction was seen in the UKA. All scores were significantly higher for UKA than for TKA, converted UKA, and revised TKA. None of the scores showed a significant inferiority of converted UKA to TKA. In the case of revision, two scores showed significantly better results for converted UKA than for revised TKA. Conclusions Our results indicated that patients initially treated with UKA did not have significantly worse functional outcomes after conversion to TKA, given the use of identical standard implants. This highlights the effectiveness of UKA as a therapeutic option with outcomes superior to those of primary TKA and the importance of a bone-sparing procedure. Conversely, revision TKA is linked to poorer functional outcomes compared to both primary arthroplasties.

Abstract The Sustainable Development Goal 8, “Decent Work and Economic Growth,” (SDG8) has crucial significance for developing nations as they grapple with the dual challenges of fostering economic growth and addressing climate change, as they are often hindered by financial constraints in advancing low-carbon transitions. Centered on SDG 8, particularly in developing countries, this paper takes Indonesia as a case study to delineate challenges and propose insights for an optimal green growth strategy. Challenges encompass fostering enduring, inclusive, and sustainable economic growth while meeting the heightened demand for electricity arising from economic priorities and strategies. The Government of Indonesia envisions low-carbon transition activities that create a substantial and dynamic workforce while preserving natural resources and the environment. The government wishes to leverage international green finance opportunities to mobilize economically stimulating capital while concurrently strengthening domestic investment capacities for future needs. In conclusion, this paper not only analyzes current challenges but also outlines prospective pathways to achieve sustainability.

MuscleX is an integrated, open-source computer software suite for data reduction of X-ray fiber diffraction patterns from striated muscle and other fibrous systems. It is written in Python and runs on Linux, Microsoft Windows or macOS. Most modules can be run either from a graphical user interface or in a `headless mode' from the command line, suitable for incorporation into beamline control systems. Here, we provide an overview of the general structure of the MuscleX software package and describe the specific features of the individual modules as well as examples of applications.

Since its establishment in North America around 2013, the east-Asian spider Trichonephila clavata has expanded its range to 120,000 km2. We used ‘MaxEnt’ species distribution models (SDMs) to assess the potential range and invasive process of T. clavata based on its climatic niche preferences. Results reveal T. clavata exhibits a preference for climatic niches between subtropical and temperate latitudes, with high suitability primarily forecasted in montane forests and coastal regions spanning latitudes of 30–50 degrees. Geographic projections indicate high risk of expansion beyond the current invasive range. Areas with over 50% suitability are predicted as far north as 45–50° N, reaching into southern Canada, while the southern extent approaches the Gulf Coast. Response curves show peak suitability occurs at below-freezing temperatures for the minimum temperature of the coldest month. Similar drivers of distribution between native and invasive models, and an invasive niche occurring within the native range, each suggest niche conservatism for invasive populations. Overall, the vast regions of climatically suitable habitat predicted in North America indicates a highly permissive climate, highlighting the need for further research on biotic factors and management strategies to mitigate spread and impacts.

ABSTRACTIntroduction Malaria represents a public health challenge in tropical and subtropical regions, and currently deployed control strategies are likely insufficient to drive elimination of malaria. Development and improvement of malaria vaccines might be key to reduce disease burden. Vaccines targeting asexual blood stages of the parasite have shown limited efficacy when studied in human trials conducted over the past decades.Areas covered Vaccine candidates based on the merozoite surface protein 1 (MSP1) were initially envisioned as one of the most promising approaches to provide immune protection against asexual blood-stage malaria. Successful immunization studies in monkey involved the use of the full-length MSP1 (MSP1FL) as vaccine construct. Vaccines using MSP1FL for immunization have the potential benefit of including numerous conserved B-cell and T-cell epitopes. This could result in improved parasite strain-transcending, protective immunity in the field. We review outcomes of clinical trials that utilized a variety of MSP1 constructs and formulations, including MSP1FL, either alone or in combination with other antigens, in both animal models and humans.Expert opinion Novel approaches to analyze breadth and magnitude of effector functions of MSP1-targeting antibodies in volunteers undergoing experimental vaccination and controlled human malaria infection will help to define correlates of protective immunity.

A series of new aromatic substituted indanone and indanol building blocks have been prepared and are anticipated to aid future drug discovery studies. In total, seven compounds (7, 12–17) are expounded on, and all have been fully characterized. In doing so, we have shown multiple examples of highly chemoselective reactions. One example employed an adaptation of Fujioka’s chemoselective reduction methodology, allowing an ester to be reduced in the presence of a ketone. In another example, an uncommon benzylic methyl group to aldehyde oxidation was demonstrated for two different compounds. These and other chemoselective interconversions allowed us to identify compound (12) as a remarkably flexible springboard for accessing a diverse array of indan-based building blocks (13–17).

Abstract Dementia and cancer are multifactorial, widely-feared, age-associated clinical syndromes that are increasing in prevalence. There have been major breakthroughs in clinical cancer research leading to some effective treatments, whereas the field of dementia has achieved comparatively limited success in clinical research. The lessons of cancer research may help those in the dementia research field in confronting some of the dilemmas faced when the clinical care regimen is not entirely safe or efficacious. Cancer clinical trials have assumed that untreated individuals with cancer are at high risk for morbidity and mortality after primary diagnoses. Thus, patients deserve a choice of clinical interventions, either standard of care or experimental, even if the benefits are not certain and the therapy’s side effects are potentially severe. The prognosis for many individuals at risk for dementia carries a correspondingly high level of risk for both mortality and severe morbidity, particularly if one focuses on “health-span” rather than lifespan. Caregivers and patients can be strongly impacted by dementia and the many troubling associated symptoms that often go well beyond amnesia. Polls, surveys, and a literature on “dementia worry” strongly underscore that the public fears dementia. While there are institutional and industry hurdles that complicate enrollment in randomized trials, the gravity of the future morbidity and mortality inherent in a dementia diagnosis may require reconsideration of the current protective stance that limits the freedom of at-risk individuals (either symptomatic or asymptomatic) to participate and potentially benefit from ongoing clinical research. There is also evidence from both cancer and dementia research that individuals enrolled in the placebo arms of clinical trials have unexpectedly good outcomes, indicating that participation in clinical trial can have medical benefits to enrollees. To highlight aspects of cancer clinical research that may inform present and future dementia clinical research, this review highlights three main themes: the risk of side effects should be weighed against the often dire consequences of non-treatment; the desirability of long-term incremental (rather than “magic bullet”) clinical advances; and, the eventual importance of combination therapies, reflecting that the dementia clinical syndrome has many underlying biological pathways.

Abstract PARP inhibitor (PARPi) therapy has transformed outcomes for patients with homologous recombination DNA repair (HRR) deficient ovarian cancers, for example those with BRCA1 or BRCA2 gene defects. Unfortunately, PARPi resistance is common. Multiple resistance mechanisms have been described, including secondary mutations that restore the HR gene reading frame. BRCA1 splice isoforms △11 and △11q can contribute to PARPi resistance by splicing out the mutation-containing exon, producing truncated, partially functional proteins. However, the clinical impacts and underlying drivers of BRCA1 exon skipping are not fully understood. We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi. BRCA1 exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs) that drive exon skipping, confirmed using qRT-PCR, RNA sequencing, immunoblotting and minigene modelling. CRISPR/Cas9-mediated disruption of splicing functionally validated exon skipping as a mechanism of PARPi resistance. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials. Few PARPi resistance mechanisms have been confirmed in the clinical setting. While secondary/reversion mutations typically restore a gene’s reading frame, we have identified secondary mutations in patient cohorts that hijack splice sites to enhance mutation-containing exon skipping, resulting in the overexpression of BRCA1 hypomorphs, which in turn promote PARPi resistance. Thus, BRCA1 SSMs can and should be clinically monitored, along with frame-restoring secondary mutations.

Abstract Given Indonesia’s abundant biomass resources, co-firing biomass presents an opportunity to reduce coal plant carbon emissions. However, the emissions profile of this strategy depends upon biomass sourcing, which, if derived from non-waste biomass (purpose-grown at plantations), could induce substantial land use change emissions, shifting emissions offset from coal plants to land. Here we use a plant-level supply-demand and combustion-cycle assessment to investigate whether available biomass in Indonesia from agricultural, forestry, and municipal waste alone can meet feedstock requirements for co-firing at various ratios throughout the year and across the archipelago. Our results indicate that incorporating existing biomass waste into coal plants reduces carbon emissions minimally without additional deforestation, meeting co-firing demand only at low ratios. However, competition with alternative uses and limited biomass supply in eastern provinces, where coal capacity is growing, preclude meeting demand at higher ratios without substantial land use change emissions.

While there are a number of available reference and testing materials for micro- and nanoplastic (MNP) studies in toxicology, they are not well-characterized and do not cover all major polymer types that may potentially pollute the environment. This review article will address the question of why we need properly designed synthesized micro- and nanoplastics with a core–shell structure (with organic–inorganic units) and provide researchers with a scientific basis for the design of synthesized MNP particles. It will include a list of commercially available MNPs, an overview of the theoretical background to polymer particle synthesis, and an analysis of the advantages and disadvantages of MNP preparation methods, namely, fragmentation and synthesis, along with examples of synthesized MNP particles. The current study will demonstrate that polystyrene is one of the most prevalent MNP particle types among reference materials from certification bodies and among testing particles synthesized by chemical scientists. Nevertheless, the global industrial production of polystyrene represents approximately 5% of the total, and it is not a dominant plastic type in the textile or packaging industries. In contrast to mechanically fragmented MNP particles, the synthesis approach offers the potential to control the physico-chemical properties, enabling the more selective detection and quantification, as well as a greater comparability of the results amongst toxicological studies.

Abstract Background The protein C system regulates blood coagulation, inflammation, and vascular integrity. AB002 is an injectable protein C activating enzyme under investigation to safely prevent and treat thrombosis. In preclinical models, AB002 is antithrombotic, cytoprotective, and anti-inflammatory. Since prophylactic use of heparin is contraindicated during hemodialysis in some end-stage renal disease (ESRD) patients, we propose using AB002 as a short-acting alternative to safely limit blood loss due to clotting in the dialysis circuit. Methods This phase 2, randomized, double-blind, placebo-controlled, single-dose study evaluates the safety and tolerability of AB002 administered into the hemodialysis line of ESRD patients during hemodialysis at one study center in the United States (ClinicalTrials.gov: NCT03963895). In this study, 36 patients were sequentially enrolled into two cohorts and randomized to AB002 or placebo in a 2:1 ratio. In cohort 1, patients received 1.5 µg/kg AB002 (n = 12) or placebo (n = 6); in cohort 2, patients received 3 µg/kg AB002 (n = 12) or placebo (n = 6). Patients underwent five heparin-free hemodialysis sessions over 10 days and were dosed with AB002 or placebo during session four. Results Here we show that AB002 is safe and well-tolerated in ESRD patients, with no treatment-related adverse events. Clinically relevant bleeding did not occur in any patient, and the time to hemostasis at the vascular access sites is not affected by AB002. Conclusions As far as we are aware, this proof-of-concept study is the first clinical trial assessing the therapeutic potential of protein C activation. The results herein support additional investigation of AB002 to safely prevent and treat thrombosis in at-risk populations.

Abstract Background The percentage of elderly trauma patients under anticoagulation and antiplatelet agents has been rising lately. As newer agents are introduced, each comes with its own advantages and precautions. Our study covered elderly patients admitted to the ED with maxillofacial trauma while on anticoagulation (AC) or antiplatelet therapy (APT). We aimed to investigate the demographic characteristics, causes, and types of maxillofacial trauma, along with concomitant injuries, duration of hospitalisation, haemorrhagic complications, and the overall costs of care in the emergency department (ED). Methods Data were gathered from the ED of Bern University Hospital. In this retrospective analysis, patients over 65 of age were included, who presented at our ED with maxillofacial trauma between 2013 and 2019 while undergoing treatment with therapeutic AC/APT. Results The study involved 188 patients with a median age of 81 years (IQR: 81 [74; 87]), of whom 55.3% (n=104) were male. More than half (54.8%, n=103) were aged 80 years or older. Cardiovascular diseases were present in 69.7% (n=131) of the patients, with the most common indications for AC/APT use being previous thromboembolic events (41.5%, n=78) and atrial fibrillation (25.5%, n=48). The predominant cause of facial injury was falls, accounting for 83.5% (n=157) of cases, followed by bicycle accidents (6.9%, n=13) and road-traffic accidents (5.3%, n=10). The most common primary injuries were fractures of the orbital floor and/or medial/lateral wall (60.1%, n=113), zygomatic bone (30.3%, n=57), followed by isolated orbital floor fractures (23.4%, n=44) and nasal bone fractures (19.1%, n=36). Fractures of the mandible occurred in 14.9% (n=28). Facial hematomas occurred in 68.6% of patients (129 cases), primarily in the midface area. Relevant facial bleeding complications were intracerebral haemorrhage being the most frequent (28.2%, n=53), followed by epistaxis (12.2%, n=23) and retrobulbar/intraorbital hematoma (9%, n=17). Sixteen patients (8.5%) experienced heavy bleeding that required emergency treatment. The in-hospital mortality rate was 2.1% (4 cases). Conclusions This study indicates that falls are the leading cause of maxillofacial trauma in the elderly, with the most common diagnoses being orbital, zygomatic, and nasal fractures. Haemorrhagic complications primarily involve facial hematomas, especially in the middle third of the face, with intracerebral haemorrhage being the second most frequent. Surgical intervention for bleeding was required in 8.5% of cases. Given the aging population, it is essential to improve prevention strategies and update safety protocols, particularly for patients on anticoagulant/antiplatelet therapy (AC/APT). This can ensure rapid diagnostic imaging and prompt treatment in emergencies.

Abstract Posttraumatic stress disorder (PTSD) can develop after trauma exposure. Some studies report that women develop PTSD at twice the rate of men, despite greater trauma exposure in men. Lipids and their metabolites (lipidome) regulate a myriad of key biological processes and pathways such as membrane integrity, oxidative stress, and neuroinflammation in the brain by maintaining neuronal connectivity and homeostasis. In this study, we analyzed the lipidome of 40 adults with PTSD and 40 trauma-exposed non-PTSD individuals (n = 20/sex/condition; 19–39 years old). Plasma samples were analyzed for lipidomics using Quadrupole Time-of-Flight (QToF) mass spectrometry. Additionally, ~ 90 measures were collected, on sleep, and mental and physical health indices. Poorer sleep quality was associated with greater PTSD severity in both sexes. The lipidomics analysis identified a total of 348 quantifiable known lipid metabolites and 1951 lipid metabolites that are yet unknown; known metabolites were part of 13 lipid subclasses. After adjusting for BMI and sleep quality, in women with PTSD, only one lipid subclass, phosphatidylethanolamine (PE) was altered, whereas, in men with PTSD, 9 out of 13 subclasses were altered compared to non-PTSD women and men, respectively. Severe PTSD was associated with 22% and 5% of altered lipid metabolites in men and women, respectively. Of the changed metabolites, only 0.5% measures (2 PEs and cholesterol) were common between women and men with PTSD. Several sphingomyelins, PEs, ceramides, and triglycerides were increased in men with severe PTSD. The correlations between triglycerides and ceramide metabolites with cholesterol metabolites and systolic blood pressure were dependent upon sex and PTSD status. Alterations in triglycerides and ceramides are linked with cardiac health and metabolic function in humans. Thus, disturbed sleep and higher body mass may have contributed to changes in the lipidome found in PTSD.

Abstract The primary obstacle to curing HIV-1 is a reservoir of CD4+ cells that contain stably integrated provirus. Previous studies characterizing the proviral landscape, which have been predominantly conducted in males in the United States and Europe living with HIV-1 subtype B, have revealed that most proviruses that persist during antiretroviral therapy (ART) are defective. In contrast, less is known about proviral landscapes in females with non-B subtypes, which represents the largest group of individuals living with HIV-1. Here, we analyze genomic DNA from resting CD4+ T-cells from 16 female and seven male Ugandans with HIV-1 receiving suppressive ART (n = 23). We perform near-full-length proviral sequencing at limiting dilution to examine the proviral genetic landscape, yielding 607 HIV-1 subtype A1, D, and recombinant proviral sequences (mean 26/person). We observe that intact genomes are relatively rare and clonal expansion occurs in both intact and defective genomes. Our modification of the primers and probes of the Intact Proviral DNA Assay (IPDA), developed for subtype B, rescues intact provirus detection in Ugandan samples for which the original IPDA fails. This work will facilitate research on HIV-1 persistence and cure strategies in Africa, where the burden of HIV-1 is heaviest.

Abstract Colorectal cancer is one of the top contributors to cancer-related deaths in the United States, with over 100,000 estimated cases in 2020 and over 50,000 deaths. The most common screening technique is minimally invasive colonoscopy using either reflected white light endoscopy or narrow-band imaging. However, current imaging modalities have only moderate sensitivity and specificity for lesion detection. We have developed a novel fluorescence excitation-scanning hyperspectral imaging (HSI) approach to sample image and spectroscopic data simultaneously on microscope and endoscope platforms for enhanced diagnostic potential. Unfortunately, fluorescence excitation-scanning HSI datasets pose major challenges for data processing, interpretability, and classification due to their high dimensionality. Here, we present an end-to-end scalable Artificial Intelligence (AI) framework built for classification of excitation-scanning HSI microscopy data that provides accurate image classification and interpretability of the AI decision-making process. The developed AI framework is able to perform real-time HSI classification with different speed/classification performance trade-offs by tailoring the dimensionality of the dataset, supporting different dimensions of deep learning models, and varying the architecture of deep learning models. We have also incorporated tools to visualize the exact location of the lesion detected by the AI decision-making process and to provide heatmap-based pixel-by-pixel interpretability. In addition, our deep learning framework provides wavelength-dependent impact as a heatmap, which allows visualization of the contributions of HSI wavelength bands during the AI decision-making process. This framework is well-suited for HSI microscope and endoscope platforms, where real-time analysis and visualization of classification results are required by clinicians.

Abstract Cytokinesis is the final step of the cell division cycle that leads to the formation of two new cells. Successful cytokinesis requires significant remodelling of the plasma membrane by spatially distinct β- and γ-actin networks. These networks are generated by the formin family of actin nucleators, DIAPH3 and DIAPH1 respectively. Here we show that β- and γ-actin perform specialized and non-redundant roles in cytokinesis and cannot substitute for one another. Expression of hybrid DIAPH1 and DIAPH3 proteins with altered actin isoform specificity relocalized cytokinetic actin isoform networks within the cell, causing cytokinetic failure. Consistent with this we show that β-actin networks, but not γ-actin networks, are required for the maintenance of non-muscle myosin II and RhoA at the cytokinetic furrow. These data suggest that independent and spatially distinct actin isoform networks form scaffolds of unique interactors that facilitate localized biochemical activities to ensure successful cell division.

The conformational ensemble and function of intrinsically disordered proteins (IDPs) are sensitive to their solution environment. The inherent malleability of disordered proteins, combined with the exposure of their residues, accounts for this sensitivity. One context in which IDPs play important roles that are concomitant with massive changes to the intracellular environment is during desiccation (extreme drying). The ability of organisms to survive desiccation has long been linked to the accumulation of high levels of cosolutes such as trehalose or sucrose as well as the enrichment of IDPs, such as late embryogenesis abundant (LEA) proteins or cytoplasmic abundant heat-soluble (CAHS) proteins. Despite knowing that IDPs play important roles and are co-enriched alongside endogenous, species-specific cosolutes during desiccation, little is known mechanistically about how IDP-cosolute interactions influence desiccation tolerance. Here, we test the notion that the protective function of desiccation-related IDPs is enhanced through conformational changes induced by endogenous cosolutes. We find that desiccation-related IDPs derived from four different organisms spanning two LEA protein families and the CAHS protein family synergize best with endogenous cosolutes during drying to promote desiccation protection. Yet the structural parameters of protective IDPs do not correlate with synergy for either CAHS or LEA proteins. We further demonstrate that for CAHS, but not LEA proteins, synergy is related to self-assembly and the formation of a gel. Our results suggest that functional synergy between IDPs and endogenous cosolutes is a convergent desiccation protection strategy seen among different IDP families and organisms, yet the mechanisms underlying this synergy differ between IDP families.

Abstract BackgroundEffective interprofessional teamwork is vital for ensuring high-quality patient care, especially in emergency medicine. However, interprofessional education often fails to facilitate meaningful interaction among health care disciplines. It is therefore imperative to afford early opportunities for cultivating interprofessional teamwork skills. While in-person simulation-based training has been shown to improve performance, this is resource-intensive, especially if it involves multiple professions. Virtual reality (VR)–based training is an innovative instructional approach that demands fewer resources and offers the flexibility of location-independent learning. ObjectiveThis study aimed to develop and evaluate the acceptance, learning outcome, and feasibility of an interprofessional team (INTEAM) training course that included a VR simulation of a neurological emergency case. MethodsThis 1-group study used a pre- and posttest design to evaluate the 2-hour INTEAM training course for nursing and medical students. The course included an e-learning part, VR simulation, and debriefing. The main learning objectives were derived from the entrustable professional activity 6, namely to handle a common problem in emergency medicine (headache due to subarachnoid hemorrhage and epileptic seizure) that requires interprofessional collaboration, including a structured handover. We used validated and self-constructed questionnaires, pre- and posttests, and open questions to assess the acceptance, learning outcome, and feasibility of the course. ResultsThe data of 42 students (21 nursing and 21 medical students) were analyzed and showed good usability in the System Usability Scale (median 72.5, IQR 65‐80). The perception of usefulness (median 6, IQR 5.8‐6.9) and ease of use (median 5.9, IQR 5.1‐6.3) was good among all students. There was a significant increase in the handover performance from pre- (median 8, IQR 6‐9) to posttraining (median 8, IQR 7‐9; zPrzPr ConclusionsThe new INTEAM training course was well received by nursing and medical students. The handover skills and confidence in caring for patients with seizures were improved after the course. Despite technical challenges with the VR simulations, none required termination, and this demonstrates that our approach is feasible. These promising results encourage the use of VR simulations for team training in the education of nursing and medical students.

Passive acoustic monitoring of soundscapes and biodiversity produces vast amounts of audio recordings, but the management and analyses of these raw data present technical challenges. A multitude of software solutions exist, but none can fulfil all purposes required for the management, processing, navigation, and analysis of acoustic data. The field of ecoacoustics needs a software tool that is free, evolving, and accessible. We take a step in that direction and present ecoSound-web: an open-source, online platform for ecoacoustics designed and built by ecologists and software engineers. ecoSound-web can be used for storing, re-sampling, organising, analysing, and sharing soundscape recording or metadata projects. Specifically, it allows manual annotation of soniferous animals and soundscape components, automatic annotation with deep-learning models for all birds and for UK bat species, peer-reviewing annotations, analysing audio in time and frequency dimensions, computing alpha acoustic indices, and providing reference sound libraries for different taxa. We present ecoSound-web’s structure and features, and describe its operation for typical use cases such as sampling bird and bat communities, using a primate call library, and the analysis of soundscape components and acoustic indices. ecoSound-web is available from: https://github.com/ecomontec/ecoSound-web

Alpine rivers are among the most heavily modified ecosystems in Europe. Following massive interventions in the 18th and 19th centuries, many plant species specialized in these challenging environments declined and are now endangered or even locally extinct. Today, attempts are being made to reintroduce these species as part of restoration measures, but only a few are successful. The selection of potential sites for reintroduction is commonly intuitive and based on practical considerations, while a prior scientific assessment of habitat availability and habitat connectivity is lacking. To increase the success of future reintroductions, we employ a habitat suitability model and subsequent habitat connectivity analysis to identify promising regions and patches for reintroduction within a riverscape. We demonstrate this approach using the Alpine river specialists Chondrilla chondrilloides and Myricaria germanica in three differently degraded and one restored section of the large Alpine river Isar. All river sections provide habitats for both species, but with increasing degradation, habitats become fewer and less connected. For the species with a narrower habitat niche and lower dispersal ability, suitable and connected patches that support a self-sustained metapopulation are only found in the near-natural sections. Despite an improvement in the habitat situation, the patch size in the restored section is too small, and the patches are too scattered to support a successful reintroduction of the species. We show that this evidence-based approach outperforms an intuitive selection of out-planting sites. The results further underline the importance of using scientific habitat analysis to increase the success of reintroduction measures.

Introduction Snakebite envenoming (SBE) results in over 500 000 deaths or disabling injuries annually. Varespladib methyl, an oral inhibitor of secretory phospholipase A2, is a nearly ubiquitous component of snake venoms. We conducted a phase II clinical trial to assess efficacy and safety of oral varespladib methyl in patients bitten by venomous snakes.Methods This double-blind, randomised, placebo-controlled trial enrolled patients in emergency departments in India and the USA. Patients with SBE were randomly assigned (1:1) to receive varespladib methyl or placebo two times per day for 1 week. All patients received standard of care, including antivenom. The primary outcome was change in the composite Snakebite Severity Score (SSS) measuring the severity of envenoming, from baseline to the average composite SSS at 6 and 9 hours.Results Among 95 patients randomised August 2021 through November 2022, the most common snakebites were from Russell’s vipers (n=29), copperheads (n=18) and rattlesnakes (n=14). The SSS improved from baseline to the average at 6 and 9 hours by 1.1 (95% CI, 0.7 to 1.6) in the varespladib group versus 1.5 (95% CI, 1.0 to 2.0) in the placebo group (difference −0.4, 95% CI, −0.8 to 0.1, p=0.13). While key secondary outcomes were not statistically different by treatment group, benefit was seen in the prespecified subgroup initiating study drug within 5 hours of bite (n=37). For this early treatment group, clinically important differences were observed for illness severity over the first week, patient-reported function on days 3 and 7 and complete recovery. No death or treatment emergent serious adverse event occurred.Conclusion For emergency department treatment of snakebites, the addition of varespladib to antivenom did not find evidence of difference for the primary outcome based on the SSS. A potentially promising signal of benefit was observed in patients initiating treatment within 5 hours of snakebite.

Abstract Age is a prominent risk factor for cardiometabolic disease, often leading to heart structural and functional changes. However, precise molecular mechanisms underlying cardiac remodeling and dysfunction exclusively resulting from physiological aging remain elusive. Previous research demonstrated age‐related functional alterations in baboons, analogous to humans. The goal of this study is to identify early cardiac molecular alterations preceding functional adaptations, shedding light on the regulation of age‐associated changes. Unbiased transcriptomics of left ventricle samples are performed from female baboons aged 7.5–22.1 years (human equivalent ≈30–88 years). Weighted‐gene correlation network and pathway enrichment analyses are performed, with histological validation. Modules of transcripts negatively correlated with age implicated declined metabolism‐oxidative phosphorylation, tricarboxylic acid cycle, glycolysis, and fatty‐acid β‐oxidation. Transcripts positively correlated with age suggested a metabolic shift toward glucose‐dependent anabolic pathways, including hexosamine biosynthetic pathway (HBP). This shift is associated with increased glycosaminoglycan synthesis, modification, precursor synthesis via HBP, and extracellular matrix accumulation, verified histologically. Upregulated extracellular matrix‐induced signaling coincided with glycosaminoglycan accumulation, followed by cardiac hypertrophy‐related pathways. Overall, these findings revealed a transcriptional shift in metabolism favoring glycosaminoglycan accumulation through HBP before cardiac hypertrophy. Unveiling this metabolic shift provides potential targets for age‐related cardiac diseases, offering novel insights into early age‐related mechanisms.

Background In 2021 we launched the BronchStart study, which collected information on 17,899 presentations in children with serious respiratory tract infections following the release of lockdown restrictions. Our study informed the Joint Committee on Vaccination and Immunisation’s decision to recommend the introduction maternal respiratory syncytial virus (RSV) vaccination, which was introduced in the United Kingdom in August/September 2024. Study question We modified our original protocol to conduct a United Kingdom-wide assessment of maternal vaccination against RSV. Methods and likely impact We will conduct a multi-centre study, utilising the PERUKI network used in the original BronchStart study, to assess the effectiveness of maternal vaccination using a test-negative study design. We will gather detailed clinical information on children admitted with bronchiolitis in the post-RSV vaccination era, and understand possible reasons for incomplete vaccine uptake.

Florida’s coral reefs are facing a multi-year outbreak of stony coral tissue loss disease (SCTLD) with dramatic consequences for coral communities. However, potential anthropogenic and environmental drivers of SCTLD progression and severity remain poorly understood. This study was designed to determine the potential impacts of nutrient amendments on the progression and spread of SCTLD on reefs in Southeast Florida. In situ fertilizer amendments with 30 g of Osmocote™ slow-release fertilizer were used to mimic the effects of agricultural and urban runoff. Fifteen healthy and thirty SCTLD-affected Montastraea cavernosa coral colonies were tagged and divided into three experimental groups: apparently healthy colonies, SCTLD-affected nutrient-amended colonies, and SCTLD-affected control colonies. SCTLD lesion progression, coral tissue loss, and disease prevalence were tracked over a 30-day nutrient amendment period and for an additional 40 days after nutrient amendment removal to determine if there were any latent or recovery effects. Coral tissue loss was tracked over time using Structure-from-Motion photogrammetry and disease prevalence was recorded from diver surveys within a 3-m radius surrounding five centroid colonies from each experimental group. Throughout the experiment, temperature, nutrient concentrations, and SCTLD status of the coral colonies were also monitored. Ultimately, we observed no significant differences in SCTLD progression or surrounding SCTLD prevalence between the nutrient-amended and control groups, suggesting that nutrient amendment had no effect on SCTLD severity during this experiment in Southeast Florida.

Reducing the risk of high-grade primary graft dysfunction (PGD) is vital to achieve acceptable short- and long-term outcomes for recipients following lung transplantation. However, the utilization of injured lung allografts, which may confer a higher risk of PGD, must be considered due to the disparity between the increasing number of patients requiring lung transplantation and the limited donor pool. We describe a case in which highly marginal lung allografts were utilized with a good post-transplant outcome. Donor–recipient PGD risk compatibility was taken into consideration. Normothermic ex vivo lung perfusion (EVLP) was utilized to functionally assess the allografts. A second cold ischemia time following EVLP was avoided by converting the EVLP mode to a hypothermic oxygenated perfusion setup from which the lungs were transplanted directly. We attempted to mitigate lung ischemia-reperfusion injury in the recipient by employing cytokine adsorption both during the EVLP and intraoperatively during the implant procedure. In this case report, we describe our hypothermic oxygenated perfusion setup on EVLP for the first time. Furthermore, we describe the utilization of cytokine adsorption in two phases of the same transplant process.

ABSTRACT Group A Streptococcus (GAS) necrotizing fasciitis (NF) is a difficult-to-treat bacterial infection associated with high morbidity and mortality despite extensive surgery and targeted antibiotic treatment. Difficult-to-treat infections are often characterized by the presence of bacteria surviving prolonged antibiotic exposure without displaying genetic resistance, referred to as persisters. In the present study, we investigated the presence of GAS persisters in tissue freshly debrided from patients as well as in an in vivo mouse model of NF and examined the phenomenon of antibiotic tolerance. Time-lapse imaging of GAS plated directly upon isolation from NF debrided tissue and an antibiotic challenge-based persisters assay were used to assess the presence of persisters. We show for the first time that GAS recovered directly from freshly debrided NF tissue is characterized by heterogeneous and overall delayed colony appearance time, suggesting the presence of persisters. Acidic pH or nutrient stress exposure, mimicking the NF-like environment in vitro, led to a similar phenotypic heterogeneity and resulted in enhanced survival upon antibiotic challenge, confirming the presence of GAS persisters. GAS persisters might contribute to NF treatment failure, despite extensive surgery and adequate antibiotic treatment.IMPORTANCEDifficult-to-treat and recurrent infections are a global problem burdening society and the health care system alike. Unraveling the mechanisms by which bacteria can survive antibiotic treatment without developing genetic resistance is of utmost importance to lay the foundation for new, effective therapeutic approaches. For the first time, we describe the phenomenon of antibiotic tolerance in group A Streptococcus (GAS) isolated from necrotizing fasciitis (NF) patients. Dormant, non-replicating cells (persisters) are tolerant to antibiotics and their occurrence in vivo is reported in an increasing number of bacterial species. Tailored treatment options, including the use of persisters-targeting drugs, need to be developed to specifically target dormant bacteria causing difficult-to-treat and recurrent infections.

Despite decades of intense research, our understanding of the correlates of protection against Salmonella Typhi (S. Typhi) infection and disease remains incomplete. T follicular helper cells (TFH), an important link between cellular and humoral immunity, play an important role in the development and production of high affinity antibodies. While traditional TFH cells reside in germinal centers, circulating TFH (cTFH) (a memory subset of TFH) are present in blood. We used specimens from a typhoid controlled human infection model whereby participants were immunized with Ty21a live attenuated S. Typhi vaccine and then challenged with virulent S. Typhi. Some participants developed typhoid disease (TD) and some did not (NoTD), which allowed us to assess the association of cTFH subsets in the development and prevention of typhoid disease. Of note, the frequencies of cTFH were higher in NoTD than in TD participants, particularly 7 days after challenge. Furthermore, the frequencies of cTFH2 and cTFH17, but not cTFH1 subsets were higher in NoTD than TD participants. However, we observed that ex-vivo expression of activation and homing markers were higher in TD than in NoTD participants, particularly after challenge. Moreover, cTFH subsets produced higher levels of S. Typhi-specific responses (cytokines/chemokines) in both the immunization and challenge phases. Interestingly, unsupervised analysis revealed unique clusters with distinct signatures for each cTFH subset that may play a role in either the development or prevention of typhoid disease. Importantly, we observed associations between frequencies of defined cTFH subsets and anti-S. Typhi antibodies. Taken together, our results suggest that circulating TFH2 and TFH17 subsets might play an important role in the development or prevention of typhoid disease. The contribution of these clusters was found to be distinct in the immunization and/or challenge phases. These results have important implications for vaccines aimed at inducing long-lived protective T cell and antibody responses.

ABSTRACT In 2000, Cleide Costa published a paper presenting the state of knowledge of the Neotropical Coleopte ra, with a focus on the Brazilian fauna. Twenty-four years later, thanks to the development of the Coleoptera section of the Taxonomic Catalog of the Brazilian Fauna (CTFB - Catálogo Taxonômico da Fauna do Brasil) through the collaboration of 100 coleopterists from all over the globe, we can build on Costa’s work and present an updated overview of the state of knowledge of the beetles from Brazil. There are currently 35,699 species in 4,958 genera and 116 families known to occur in the country, including representatives of all extant suborders and superfamilies. Our data show that the Brazilian beetle fauna is the richest on the planet, concentrating 9% of the world species diversity, with some estimates accounting to up to 15% of the global total. The most diverse family in numbers of genera is Cerambycidae (1,056 genera), while in number of species it is Chrysomelidae (6,079 species). Conotrachelus Dejean, 1835 (Curculionidae) is the most species-rich genus, with 570 species. The French entomologist Maurice Pic is the author who has contributed the most to the naming of species recorded from Brazil, with 1,794 valid names in 36 families, whereas the Brazilians Ubirajara R. Martins and Maria Helena M. Galileo are the only ones among the top-ten authors to have named species in the 21st century. Currently, approximately 144 new species of Brazilian beetles are described each year, and this average is projected to increase in the next decade to 180 species per year, or about one new Brazilian beetle every two days.

Interest in the microbiome and its correlation with different neurological diseases has grown significantly over the past decade. The gut microbiome contains a vast array of diverse organisms living in the gastrointestinal (GI) tract. Predominantly composed of bacteria, the gut microbiome helps regulate homeostasis and metabolism in the host, aiding in immune system development as well as vitamin and nutrient absorption. Studies suggest that, in addition to providing humans with these physiological benefits, the gut microbiome is also linked to and communicates with the brain via the gut-brain axis (GBA). Long-standing research on the GBA has demonstrated that the GI tract and the central nervous system are interconnected through both neurological and immunological signaling pathways. Recent research is expanding our understanding of the microbiome and the GBA, revealing correlations between the microbiome impact on the GBA and neurological conditions such as Alzheimer’s dementia and Lewy body dementia, going as far as to identify and highlight specific microbial species that may serve as risk or protective factors for various forms of dementia. This letter aims to highlight the current findings and recommend the use of tools such as microbial cell-free DNA testing to gain a better understanding of the role of gut dysbiosis in dementia patients.

Abstract In striated muscle, the sarcomeric protein myosin-binding protein-C (MyBP-C) is bound to the myosin thick filament and is predicted to stabilize myosin heads in a docked position against the thick filament, which limits crossbridge formation. Here, we use the homozygous Mybpc2 knockout (C2-/-) mouse line to remove the fast-isoform MyBP-C from fast skeletal muscle and then conduct mechanical functional studies in parallel with small-angle X-ray diffraction to evaluate the myofilament structure. We report that C2−/− fibers present deficits in force production and calcium sensitivity. Structurally, passive C2-/- fibers present altered sarcomere length-independent and -dependent regulation of myosin head conformations, with a shift of myosin heads towards actin. At shorter sarcomere lengths, the thin filament is axially extended in C2-/-, which we hypothesize is due to increased numbers of low-level crossbridges. These findings provide testable mechanisms to explain the etiology of debilitating diseases associated with MyBP-C.

Abstract In primates, foveal and peripheral vision have distinct neural architectures and functions. However, it has been debated if selective attention operates via the same or different neural mechanisms across eccentricities. We tested these alternative accounts by examining the effects of selective attention on the steady-state visually evoked potential (SSVEP) and the fronto-parietal signal measured via EEG from human subjects performing a sustained visuospatial attention task. With a negligible level of eye movements, both SSVEP and SND exhibited the heterogeneous patterns of attentional modulations across eccentricities. Specifically, the attentional modulations of these signals peaked at the parafoveal locations and such modulations wore off as visual stimuli appeared closer to the fovea or further away towards the periphery. However, with a relatively higher level of eye movements, the heterogeneous patterns of attentional modulations of these neural signals were less robust. These data demonstrate that the top-down influence of covert visuospatial attention on early sensory processing in human cortex depends on eccentricity and the level of saccadic responses. Taken together, the results suggest that sustained visuospatial attention operates differently across different eccentric locations, providing new understanding of how attention augments sensory representations regardless of where the attended stimulus appears.

Abstract The in vivo efficacy of polymeric nanoparticles (NPs) is dependent on their pharmacokinetics, including time in circulation and tissue tropism. Here we explore the structure-function relationships guiding physiological fate of a library of poly(amine-co-ester) (PACE) NPs with different compositions and surface properties. We find that circulation half-life as well as tissue and cell-type tropism is dependent on polymer chemistry, vehicle characteristics, dosing, and strategic co-administration of distribution modifiers, suggesting that physiological fate can be optimized by adjusting these parameters. Our high-throughput quantitative microscopy-based platform to measure the concentration of nanomedicines in the blood combined with detailed biodistribution assessments and pharmacokinetic modeling provides valuable insight into the dynamic in vivo behavior of these polymer NPs. Our results suggest that PACE NPs—and perhaps other NPs—can be designed with tunable properties to achieve desired tissue tropism for the in vivo delivery of nucleic acid therapeutics. These findings can guide the rational design of more effective nucleic acid delivery vehicles for in vivo applications.

ABSTRACT: Processing temperature has a significant influence on the composition and functionality of the resulting streams following microfiltration (MF) of skim milk. In this study, MF and diafiltration (DF) were performed at 4 or 50°C to produce β-casein (β-CN)-depleted and nondepleted (i.e., native casein profile) micellar casein isolate retentates, respectively. Microfiltration combined with extensive DF resulted in a 40% depletion of β-CN at 4°C, whereas no β-CN depletion occurred at 50°C. Microfiltration at 4°C led to higher transmission of calcium into permeates, with retentate generated at 4°C containing less total calcium compared with retentate generated at 50°C, based on the volume of retentate remaining. Higher heat stability at 120°C was measured for retentates generated at 4°C compared with those at 50°C, across all pH values measured. Retentates generated at 4°C also had significantly lower ionic calcium values at each pH compared with those generated at 50°C. Higher apparent viscosities at 4°C were measured for retentates generated at 4°C compared with retentates generated at 50°C, likely due to increased voluminosity of β-CN-depleted casein micelles. The results of this study provide new information on how changing the composition of MF retentate, by appropriate control of processing temperature and DF, can alter physicochemical properties of casein micelles, with potential implications for ingredient functionality.

Abstract Drowsiness while driving negatively impacts road safety, especially in truck drivers. The present study investigated the feasibility and alerting effects of a daylight-supplementing in-truck lighting system (DS) providing short-wavelength enriched light before, during, and after driving. In a within-participants design, eight truck drivers drove a fully-loaded truck under wintry Scandinavian conditions (low daylight levels) with a DS or placebo system for five days. Subjective and objective measures of alertness were recorded several times daily, and evening melatonin levels were recorded three times per study condition. DS significantly increased daytime light exposure without causing negative side effects while driving. In addition, no negative carry-over effects were observed on evening melatonin and sleepiness levels or on nighttime sleep quality. Moreover, objective alertness (i.e., psychomotor vigilance) before and after driving was significantly improved by bright light exposure. This effect was accompanied by improved subjective alertness in the morning. This field study demonstrated that DS was able to increase daytime light exposure in low-daylight conditions and to improve alertness in truck drivers before and after driving (e.g., during driving rest periods). Further studies are warranted to investigate the effects of daylight-supplementing in-cabin lighting on driving performance and road safety measures.

Abstract Marine heatwaves are increasing in frequency and duration, threatening tropical reef ecosystems through intensified coral bleaching events. We examined a strikingly variable spatial pattern of bleaching in Moorea, French Polynesia following a heatwave that lasted from November 2018 to July 2019. In July 2019, four months after the onset of bleaching, we surveyed > 5000 individual colonies of the two dominant coral genera, Pocillopora and Acropora, at 10 m and 17 m water depths, at six forereef sites around the island where temperature was measured. We found severe bleaching increased with colony size for both coral genera, but Acropora bleached more severely than Pocillopora overall. Acropora bleached more at 10 m than 17 m, likely due to higher light availability at 10 m compared to 17 m, or greater daily temperature fluctuation at depth. Bleaching in Pocillopora corals did not differ with depth but instead varied with the interaction of colony size and Accumulated Heat Stress (AHS), in that larger colonies (> 30 cm) were more sensitive to AHS than mid-size (10–29 cm) or small colonies (5–9 cm). Our findings provide insight into complex interactions among coral taxa, colony size, and water depth that produce high spatial variation in bleaching and related coral mortality.

Background/Aims Nonalcoholic fatty liver disease (NAFLD) is associated with a multitude of adverse outcomes. We aimed to estimate the pooled incidence of NAFLD-related adverse events. Methods We performed a systematic review and meta-analysis of cohort studies of adults with NAFLD to evaluate the pooled incidence of adverse events. Results 19,406 articles were screened, 409 full-text articles reviewed, and 79 eligible studies (1,377,466 persons) were included. Mean age was 51.47 years and body mass index 28.90 kg/m2. Baseline comorbidities included metabolic syndrome (41.73%), cardiovascular disease (CVD) (16.83%), cirrhosis (21.97%), and nonalcoholic steatohepatitis (NASH) (58.85%). Incidence rate per 1,000 person-years for mortality included: all-cause (14.6), CVD-related (4.53), non-liver cancer-related (4.53), and liver-related (3.10). Incidence for liver-related events included overall (24.3), fibrosis progression (49.0), cirrhosis (10.9), liver transplant (12.0), and hepatocellular carcinoma (HCC) (3.39). Incidence for non-liver events included metabolic syndrome (25.4), hypertension (25.8), dyslipidemia (26.4), diabetes (19.0), CVD (24.77), renal impairment (30.3), depression/anxiety (29.1), and non-liver cancer (10.5). Biopsy-proven NASH had higher incidence of HCC (P=0.043) compared to non-NASH. Higher rates of CVD and mortality were observed in North America and Europe, hypertension and non-liver cancer in North America, and HCC in Western Pacific/Southeast Asia (P

Abstract Muscle contraction is produced via the interaction of myofilaments and is regulated so that muscle performance matches demand. Myosin-binding protein C (MyBP-C) is a long and flexible protein that is tightly bound to the thick filament at its C-terminal end (MyBP-CC8C10), but may be loosely bound at its middle- and N-terminal end (MyBP-CC1C7) to myosin heads and/or the thin filament. MyBP-C is thought to control muscle contraction via the regulation of myosin motors, as mutations lead to debilitating disease. We use a combination of mechanics and small-angle X-ray diffraction to study the immediate and selective removal of the MyBP-CC1C7 domains of fast MyBP-C in permeabilized skeletal muscle. We show that cleavage leads to alterations in crossbridge kinetics and passive structural signatures of myofilaments that are indicative of a shift of myosin heads towards the ON state, highlighting the importance of MyBP-CC1C7 to myofilament force production and regulation.

Coronavirus disease 2019 (COVID-19) mRNA vaccines that have contributed to controlling the SARS-CoV-2 pandemic induce specific serum antibodies, which correlate with protection. However, the neutralizing capacity of antibodies for emerging SARS-CoV-2 variants is altered. Suboptimal antibody responses are observed in patients with humoral immunodeficiency diseases, ongoing B cell depletion therapy, and aging. Common experimental mouse models with altered B cell compartments, such as B cell depletion or deficiency, do not fully recapitulate scenarios of declining or suboptimal antibody levels as observed in humans. We report on SARS-CoV-2 immunity in a transgenic mouse model with restricted virus-specific antibodies. Vaccination of C57BL/6-Tg(IghelMD4)4Ccg/J mice with unmodified or N1mΨ-modified mRNA encoding for ancestral spike (S) protein and subsequent challenge with mouse-adapted SARS-CoV-2 provided insights into antibody-independent immunity and the impact of antibody titers on mucosal immunity. Protection against fatal disease was independent of seroconversion following mRNA vaccination, suggesting that virus-specific T cells can compensate for suboptimal antibody levels. In contrast, mRNA-induced IgG in the nasal conchae limited the local viral load and disease progression. Our results indicate that parenteral mRNA immunization can elicit nasal IgG antibodies that effectively suppress local viral replication, highlighting the potential of vaccines in controlling SARS-CoV-2 transmission and epidemiology.

Infecting humans with controlled doses of helminths, such as human hookworm (termed hookworm therapy), is proposed to prevent or treat various intestinal and extraintestinal diseases. However, full-scale clinical trials examining hookworm therapy are limited by the inability to scale-up the production of hookworm larvae to infect sufficient numbers of patients. With the aim of overcoming this challenge, this study infected four healthy individuals with hookworm larvae that had been reanimated from cryopreserved eggs to examine their viability and immunogenicity. We demonstrate that reanimated cryopreserved hookworm larvae establish a viable hookworm infection and elicit a similar immune response to larvae cultured from fresh stool. Furthermore, a refined understanding of the therapeutic mechanisms of hookworm is imperative to determine which diseases to target with hookworm therapy. To investigate potential therapeutic mechanisms, this study assessed changes in the immune cells, microbiome, and plasma metabolome in the four healthy individuals infected with cryopreserved hookworm larvae and another nine individuals infected with larvae cultured from freshly obtained stool. We identified potential immunoregulatory mechanisms by which hookworm may provide a beneficial effect on its host, including increased expression of CTLA-4 on regulatory T cells (Tregs) and upregulation of tryptophan metabolism. Furthermore, we found that a participant’s baseline microbiome predicted the severity of symptoms and intestinal inflammation experienced during a controlled hookworm infection. In summary, our findings demonstrate the feasibility of full-scale clinical trials examining hookworm therapy by minimizing the reliance on human donors and optimizing the culturing process, thereby enabling viable hookworm larvae to be mass-produced and enabling on-demand inoculation of patients. Furthermore, this study provides insights into the complex interactions between helminths and their host, which could inform the development of novel therapeutic strategies.