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Background Each year, over 340,000 diabetic patients across the world travel to Saudi Arabia for the Hajj pilgrimage. As they carried out important rituals, several complications might be encountered, particularly foot lesions. We’ve been therefore interested, through this study, in the assessment of podiatric risk in diabetic pilgrims. Methods A prospective longitudinal study was conducted in the region of Sousse, Tunisia. The evaluation of diabetic patients preparing for the pilgrimage was conducted in two phases, before and after the pilgrimage. Results Forty-three diabetic patients planning to perform pilgrimage were included in the study. Post-pilgrimage clinical exams revealed hyperkeratosis (96.8%) and superficial fungal infections (61.3%) as the most common podiatric lesions. Foot ulcers attributed to trauma from walking were found in 7% of patients. Our data showed a significant association between foot ulcer risk and lower total cholesterol (p=0.02), HDL cholesterol (p=0.02), LDL cholesterol (p=0.01), as well as higher triglyceride levels (p=0.04) only in univariate analysis. Other diabetes-related risk factors did not show significant correlations. Conclusion Given the increased risk of foot lesions in diabetic pilgrims, a thorough assessment and tailored management based on individual risk levels are essential before, during, and after the pilgrimage.

Toxoplasma gondii's propensity to infect its host and cause disease is highly dependent on its ability to modulate host cell functions. One of the strategies the parasite uses to accomplish this is via the export of effector proteins from the secretory dense granules. Dense granule (GRA) proteins are known to play roles in nutrient acquisition, host cell cycle manipulation, and immune regulation. Here, we characterize a novel dense granule protein named GRA83, which localizes to the parasitophorous vacuole (PV) in tachyzoites and bradyzoites. Disruption of GRA83 results in increased virulence, weight loss, and parasitemia during the acute infection, as well as a marked increase in the cyst burden during the chronic infection. This increased parasitemia was associated with an accumulation of inflammatory infiltrates in tissues in both acute and chronic infections. Murine macrophages infected with ∆gra83 tachyzoites produced less interleukin-12 (IL-12) in vitro, which was confirmed with reduced IL-12 and interferon-gamma in vivo. This dysregulation of cytokines correlates with reduced nuclear translocation of the p65 subunit of the nuclear factor-κB (NF-κB) complex. While GRA15 similarly regulates NF-κB, infection with ∆gra83/∆gra15 parasites did not further reduce p65 translocation to the host cell nucleus, suggesting these GRAs function in converging pathways. We also used proximity labeling experiments to reveal candidate GRA83 interacting T. gondii-derived partners. Taken together, this work reveals a novel effector that stimulates the innate immune response, enabling the host to limit the parasite burden. Importance Toxoplasma gondii poses a significant public health concern as it is recognized as one of the leading foodborne pathogens in the United States. Infection with the parasite can cause congenital defects in neonates, life-threatening complications in immunosuppressed patients, and ocular disease. Specialized secretory organelles, including the dense granules, play an important role in the parasite's ability to efficiently invade and regulate components of the host's infection response machinery to limit parasite clearance and establish an acute infection. Toxoplasma's ability to avoid early clearance, while also successfully infecting the host long enough to establish a persistent chronic infection, is crucial in allowing for its transmission to a new host. While multiple GRAs directly modulate host signaling pathways, they do so in various ways highlighting the parasite's diverse arsenal of effectors that govern infection. Understanding how parasite-derived effectors harness host functions to evade defenses yet ensure a robust infection is important for understanding the complexity of the pathogen's tightly regulated infection. In this study, we characterize a novel secreted protein named GRA83 that stimulates the host cell's response to limit infection.

Summary: Background: Viperidae snakes are responsible for many of the 94,000 deaths caused by snakebite envenoming each year. The most pathological venom component of this globally diverse family of snakes are the zinc-dependent snake venom metalloproteinase (SVMP) enzymes, which can be inhibited by the metal chelator, unithiol. A short-course oral regimen, readily available and rapidly deployed ahead of hospital admission is needed. Methods: This open-label, phase 1 clinical trial assessed the safety of single ascending oral, multiple ascending oral, and single ascending intravenous doses of unithiol in 64 healthy adult volunteers from Kilifi County, Kenya. The multiple dose stage was informed by an interim safety and pharmacokinetic analysis, and predefined target plasma concentrations. Plasma concentrations of unithiol were measured using high-performance liquid chromatography-mass spectrometry, and safety was described by full adverse event reporting. Findings: 175 individuals were screened, and 64 (median age 30 years, IQR 25–38 years) received the study drug. There were no dose limiting toxicities or serious adverse events. There were 61 solicited adverse events, 17 related unsolicited adverse events, and 53 laboratory adverse events, all of mild or moderate severity. The maximum oral dose of 1500 mg was well tolerated and associated with the following pharmacokinetic parameters: Cmax 14.7 μg/mL, Tmax 2.9 h, T1/2 18.4 h, and AUC0-∞ 204.5 μg.h/mL. Interpretation: The phase 2 recommended dose (1500 mg loading dose, followed by 900 mg doses at 6-h and 24-h) has no safety concerns, and has promising pharmacokinetic properties for clinical use. Unithiol is affordable, stable at room temperature, and has the potential to be given orally in remote rural clinics. Its further development for snakebite indication is warranted. Funding: Wellcome Trust, Bloomsbury Set, and Cures Within Reach.

Summary: Cigarette smoke exposure (CSE) increases the risk for a plethora of cancers. Recent evidence indicates that the gut microbiome can influence cancer progression by immune system modulation. Since CSE alters the gut microbiome, we hypothesized that the gut microbiome serves as a causative link between smoking and cancer growth. Through a combination of syngeneic animal models and fecal microbiota transplantation studies, we established an essential role for smoke-induced dysbiosis in cancer growth. 16s rRNA sequencing and liquid chromatography-mass spectrometry indicated a unique CSE-associated microbial and metabolomic signature. Immunophenotyping of tumor specimens and experiments in Rag1-KO and CD8-KO demonstrated that smoke-induced tumor growth requires functional adaptive immunity. Finally, utilizing gut microbial ablation strategies with broad- and narrow-spectrum antibiotics, we demonstrated the reversal of phenotypic effects of CSE. Our study provides evidence for gut microbiome as an actionable target to mitigate CSE-induced tumor promotion.

BackgroundProject-based learning (PjBL) is a widely adopted educational approach known for fostering critical skills such as collaboration, problem-solving, and self-regulated learning. Despite its global implementation across various educational levels and disciplines, there has been limited comprehensive analysis of global research trends in PjBL.ObjectiveThis study maps the global research on PjBL.MethodsWe used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, bibliometrics, and network analyses to analyze 2,273 peer-reviewed articles indexed in the Web of Science Core Collection and published between January 2014 and August 2024.ResultsOur findings show a significant increase in PjBL research over time, with an 800% growth in publications since 2014. The most frequent keywords are engineering education, higher education, and STEM, and the main research areas are Education and Educational Research, Engineering, and Computer Science. The United States of America, Spain, and China are the leading countries in publications. Additionally, the network analysis shows strong collaborations, particularly between organizations in the USA and Asia.ConclusionThis study offers a broad understanding of the global research landscape on PjBL, delivering key insights for future studies and promoting collaborative research among organizations worldwide.

BackgroundThe rapid evolution of artificial intelligence (AI) presents transformative potential for diagnostic medicine, offering opportunities to enhance diagnostic accuracy, reduce costs, and improve patient outcomes. ObjectiveThis study aimed to assess the expected future impact of AI on diagnostic medicine by comparing global researchers’ expectations using 2 cross-sectional surveys. MethodsThe surveys were conducted in September 2020 and February 2023. Each survey captured a 10-year projection horizon, gathering insights from >3700 researchers with expertise in AI and diagnostic medicine from all over the world. The survey sought to understand the perceived benefits, integration challenges, and evolving attitudes toward AI use in diagnostic settings. ResultsResults indicated a strong expectation among researchers that AI will substantially influence diagnostic medicine within the next decade. Key anticipated benefits include enhanced diagnostic reliability, reduced screening costs, improved patient care, and decreased physician workload, addressing the growing demand for diagnostic services outpacing the supply of medical professionals. Specifically, x-ray diagnosis, heart rhythm interpretation, and skin malignancy detection were identified as the diagnostic tools most likely to be integrated with AI technologies due to their maturity and existing AI applications. The surveys highlighted the growing optimism regarding AI’s ability to transform traditional diagnostic pathways and enhance clinical decision-making processes. Furthermore, the study identified barriers to the integration of AI in diagnostic medicine. The primary challenges cited were the difficulties of embedding AI within existing clinical workflows, ethical and regulatory concerns, and data privacy issues. Respondents emphasized uncertainties around legal responsibility and accountability for AI-supported clinical decisions, data protection challenges, and the need for robust regulatory frameworks to ensure safe AI deployment. Ethical concerns, particularly those related to algorithmic transparency and bias, were noted as increasingly critical, reflecting a heightened awareness of the potential risks associated with AI adoption in clinical settings. Differences between the 2 survey waves indicated a growing focus on ethical and regulatory issues, suggesting an evolving recognition of these challenges over time. ConclusionsDespite these barriers, there was notable consistency in researchers’ expectations across the 2 survey periods, indicating a stable and sustained outlook on AI’s transformative potential in diagnostic medicine. The findings show the need for interdisciplinary collaboration among clinicians, AI developers, and regulators to address ethical and practical challenges while maximizing AI’s benefits. This study offers insights into the projected trajectory of AI in diagnostic medicine, guiding stakeholders, including health care providers, policy makers, and technology developers, on navigating the opportunities and challenges of AI integration.

The application of wearable hydrogel wound patches has great potential in advancing the field of medicine. However, for high reach and large-scale utilization, the fabrication process of wearable hydrogel wound patches needs to be low-cost, reliable, and have high throughput. Therefore, the incorporation of 3D-printing technology helps in providing a starting point for flexible, high throughput, mechanically enhanced, low-cost, and reliable antibacterial wound patches. 3D-printed patches can perform antibacterial behavior while exhibiting a fast fabrication process in a time range of less than 3 h. The fabricated patch exhibited good water retention, water vapor transmission rates a porosity values indicating that it has a promising potential to be commercialized as a wound patch.

Summary: Background: Snakebite (SB) envenoming is an acute emergency requiring early care delivery. However, sometimes, patients can take several hours before receiving antivenom (AV). We conducted this study to assess the effectiveness of antivenom in the recovery of clotting parameters in patients consulting tardily after SB envenoming in French Guiana. The primary endpoint of our study was to investigate the time needed from SB to recovery from SB-induced coagulopathy. The secondary endpoint was to investigate the time needed from AV administration to recovery from SB-induced coagulopathy in patients receiving AV (late or very late administration). Methods: This prospective observational study was conducted in the Intensive Care Unit (ICU) of Cayenne General Hospital between January 2016 and September 2023. We included all patients hospitalized for SB envenoming who either did not receive AV or received it more than 6 h after SB. We excluded patients who received antivenom in less than 6 h from the SB and those who received incomplete AV doses. Findings: We included 58 patients in the No AV group, 51 in the late AV group (6 h ≤ AV

Chronic stress increases the incidence of psychiatric disorders including anxiety, depression, and posttraumatic stress disorder. Repeated Social Defeat (RSD) in mice recapitulates several key physiological, immune, and behavioral changes evident after chronic stress in humans. For instance, neurons in the prefrontal cortex, amygdala, and hippocampus are involved in the interpretation of and response to fear and threatful stimuli after RSD. Therefore, the purpose of this study was to determine how stress influenced the RNA profile of hippocampal neurons and neurons that project into the hippocampus from threat appraisal centers. Here, RSD increased anxiety-like behavior in the elevated plus maze and reduced hippocampal-dependent novel object location memory in male mice. Next, pan-neuronal (Baf53 b-Cre) RiboTag mice were generated to capture ribosomal bound mRNA (i.e., active translation) activated by RSD in the hippocampus. RNAseq revealed that there were 1694 differentially expressed genes (DEGs) in hippocampal neurons after RSD. These DEGs were associated with an increase in oxidative stress, synaptic long-term potentiation, and neuroinflammatory signaling. To further examine region-specific neural circuitry associated with fear and anxiety, a retrograde-adeno-associated-virus (AAV2rg) expressing Cre-recombinase was injected into the hippocampus of male RiboTag mice. This induced expression of a hemagglutinin epitope in neurons that project into the hippocampus. These AAV2rg-RiboTag mice were subjected to RSD and ribosomal-bound mRNA was collected from the amygdala for RNA-sequencing. RSD induced 677 DEGs from amygdala projections. Amygdala neurons that project into the hippocampus had RNA profiles associated with increased synaptogenesis, interleukin-1 signaling, nitric oxide, and reactive oxygen species production. Using a similar approach, there were 1132 DEGs in neurons that project from the prefrontal cortex. These prefrontal cortex neurons had RNA profiles associated with increased synaptogenesis, integrin signaling, and dopamine feedback signaling after RSD. Collectively, there were unique RNA profiles of stress-influenced projection neurons and these profiles were associated with hippocampal-dependent behavioral and cognitive deficits.

Abstract Tracheo‐bronchial adenoid cystic carcinoma (TBACC) is a rare disease. Its treatment is mainly surgical. We herein describe the clinical and para‐clinical varieties of TBACC as well as their surgical treatment and prognosis. We conducted a retrospective study of eight patients operated on between 1994 and 2022 and whose definitive pathological examination concluded with primary TBACC. There were three men and five women with an average age of 44 years. The bronchoscopy found a budding formation reducing the tracheal lumen at the cervical (two cases), middle (two case) and distal trachea and carina (four cases). Bronchial anastomosis resection and sleeve pneumonectomy were the most common procedures. Surgical resections R0 were achieved in five patients. Surgery followed by adjuvant radiotherapy was performed in two patients with incomplete surgical resection R1. The overall survival for all patients with primary ACC was 72% at 5 years. TBACC is a rare and low‐to‐moderate grade malignant tumour. The choice of the surgical procedure and the appropriate approach is challenging to obtain a promising prognosis.

Task-sharing holds promise for bridging gaps in access to mental healthcare; yet there remain significant challenges to scaling up task-sharing models. This formative study aimed to develop a digital platform for training non-specialist providers without prior experience in mental healthcare to deliver a brief psychosocial intervention for depression in community settings in Texas. A 5-step development approach was employed, consisting of: blueprinting, scripting, video production and digital content creation, uploading digital content to a Learning Management System and user testing. This resulted in the development of two courses, one called Foundational Skills covering the skills to become an effective counselor, and the second called Behavioral Activation covering the skills for addressing adult depression. Twenty-one participants with a range of health-related backgrounds, including 11 with prior training in mental healthcare, completed the training and joined focus group discussions offering qualitative feedback and recommendations for improving the program’s usability. Participant feedback centered around the need to make the content more interactive, to include additional engaging features, and to improve the layout and usability of the platform. The next steps will involve evaluating the training program on developing the skills of non-specialist providers and supporting its uptake and implementation.

DIII-D research is being accelerated by leveraging high performance computing (HPC) and data resources available through the National Energy Research Scientific Computing Center (NERSC) Superfacility initiative. As part of this initiative, a high-resolution, fully automated, whole discharge kinetic equilibrium reconstruction workflow was developed that runs at the NERSC for most DIII-D shots in under 20 min. This has eliminated a long-standing research barrier and opened the door to more sophisticated analyses, including plasma transport and stability. These capabilities would benefit from being automated and executed within the larger Department of Energy Advanced Scientific Computing Research program’s Integrated Research Infrastructure (IRI) framework. The goal of IRI is to empower researchers to meld DOE’s world-class research tools, infrastructure, and user facilities seamlessly and securely in novel ways to radically accelerate discovery and innovation. For transport, we are looking at producing flux matched profiles and also using particle tracing to predict fast ion heat deposition from neutral beam injection before a shot takes place. Our starting point for evaluating plasma stability focuses on the pedestal limits that must be navigated to achieve better confinement. This information is meant to help operators run more effective experiments, so it needs to be available rapidly inside the DIII-D control room. So far this has been achieved by ensuring the data is available with existing tools, but as more novel results are produced new visualization tools must be developed. In addition, all of the high-quality data we have generated has been collected into databases that can unlock even deeper insights. This has already been leveraged for model and code validation studies as well as for developing AI/ML surrogates. The workflows developed for this project are intended to serve as prototypes that can be replicated on other experiments and can be run to provide timely and essential information for ITER, as well as next stage fusion power plants.

IntroductionAcute myeloid leukemia (AML) is a rare haematological cancer with poor 5-years overall survival (OS) and high relapse rate. Leukemic cells are sensitive to Natural Killer (NK) cell mediated killing. However, NK cells are highly impaired in AML, which promote AML immune escape from NK cell immune surveillance. We made the first report of CD56neg CD16+ NK cells expansion in AML. This unconventional subset has been reported to expand in some chronic viral infections. Although it is unclear whether CD56neg NK cells expansion mechanism is common across diseases, it seems more relevant than ever to further investigate this subset, representing a potential therapeutic target.MethodsWe used PBMCs from AML patients and HV to perform mass cytometry, spectral flow cytometry, bulk RNA-seq and in vitro assays in order to better characterize CD56neg CD16+ NK cells that expand in AML.ResultsWe confirmed that CD56neg CD16+ NK cells represent a unique NK cell subset coexpressing Eomes and T-bet. CD56neg CD16+ NK cells could recover CD56 expression in vitro where they displayed unaltered NK cell functions. We previously demonstrated that CD56neg CD16+ NK cells expansion at diagnosis was associated with adverse clinical outcome in AML. Here, we validated our findings in a validation cohort of N=38 AML patients. AML patients with CD56neg CD16+ NK cells expansion at diagnosis had decreased overall survival (HR[CI95]=5.5[1.2-24.5], p=0.0251) and relapse-free survival (HR[CI95]=13.1[1.9-87.5], p=0.0079) compared to AML patients without expansion after 36 months follow-up. RNA-seq unveiled that CD56neg CD16+ NK cells were mature circulating NK cells with functional capacities. Upon expansion, CD56neg CD16+ NK cells from AML patients showed altered proteomic phenotype, with increased frequency of terminally mature CD56neg CD16+ NK cells expressing TIGIT along with decreased frequency of Siglec-7+ CD56neg CD16+ NK cells.DiscussionTaken together, our results suggest that we could harness CD56neg CD16+ NK cells cytotoxic potential in vitro to restore NK cell anti-tumor response in AML patients with CD56neg CD16+ NK cells expansion and improve patients’ prognosis. To conclude, CD56neg CD16+ NK cells represent a relevant target for future NK-cell-based immunotherapies in AML.

The literature on the research–practice gap in agriculture has evolved significantly in recent decades. Although there is a well-established body of work on how farmers adopt agricultural research outcomes and the factors that influence their adoption, research on how researchers perceive the process of transferring their results to practical applications, along with the factors that facilitate or hinder this process, remains inadequate. This study addresses this gap by conducting a systematic literature review of empirical studies on knowledge transfer and its determinants from the perspective of agricultural researchers, covering publications from 1960 to 2024. It offers two key contributions: first, an original taxonomy of the channels through which agricultural research is transferred to farmers, and second, an integrative conceptual framework that links knowledge transfer to three categories of influential factors, related to researchers’ individual characteristics, the organizational context within research institutions, and the external environment. Based on the findings, a research agenda has been developed to serve as a foundation for future investigations into persistent gaps in the field. The findings hold value for both academic and practitioner communities as they provide deeper insights to improve the understanding and practice of knowledge transfer in agriculture.