Neuromicrobiology Comes of Age: The Multifaceted Interactions between the Microbiome and the Nervous System.

The past decade has seen an explosion in our knowledge about the interactions between gut microbiota, the central nervous system, and the immune system. The gut-brain axis has recently gained much attention due to its role in regulating host physiology. This review explores recent findings concerning potential pathways linking the gut-brain axis to the initiation, pathophysiology, and development of neurological disorders. Our objective of this work is to uncover causative factors and pinpoint particular pathways and therapeutic targets that may facilitate the translation of experimental animal research into practical applications for human patients. We highlight three distinct yet interrelated mechanisms: (1) disruptions of both the intestinal and blood-brain barriers, (2) persistent neuroinflammation, and (3) the role of the vagus nerve.

Residual Popliteal Aneurysm Perfusion Leading to Embolic Complications: A Case Report.

Introduction: Surgical management of popliteal artery aneurysms has been described for half a century. Long term development of the excluded aneurysm sac in the popliteal segment however remains widely unknown, with only a few small series describing outcomes. Residual aneurysm perfusion has the potential to lead to serious complications. Report: A 63 year old man presents with skin and soft tissue necrosis of the right calf two years after proximal and distal aneurysm ligation and great saphenous vein bypass for a popliteal artery aneurysm. Computed tomography and magnetic resonance angiography show perfusion of the excluded aneurysm as well as extensive necrosis of the gastrocnemius muscle. Direct angiography of the aneurysm demonstrated retrograde aneurysm perfusion due to insufficient distal ligation with recurrent micro-embolisation to the calf via geniculate arteries. Coiling of the geniculate arteries was performed, plugging the connection to the tibiofibular trunk and embolisation of the aneurysm sac. After the intervention, no flow was seen in the aneurysm sac and the patient made full recovery. Discussion: Residual aneurysm sac perfusion can lead to complications long after successful aneurysm exclusion. Follow-up after surgery of popliteal aneurysms should include observation of the excluded aneurysm sac with control of residual blood flow. For persistent sac perfusion, aneurysm enlargement or symptoms, further treatment should be considered. Surgical aspects such as complete transection of the artery after aneurysm ligation or end to end anastomosis of the bypass may be considered, to prevent such complications.

Four-dimensional analysis of aortic root motion in normal population using retrospective multiphase computed tomography.

Aims: Aortic root motion is suspected to contribute to proximal aortic dissection. While motion of the aorta in four dimensions can be traced with real-time imaging, displacement and rotation in quantitative terms remain unknown. The hypothesis was to show feasibility of quantification of three-dimensional aortic root motion from dynamic CT imaging. Methods and results: Dynamic CT images of 40 patients for coronary assessment were acquired using a dynamic protocol. Scans were ECG-triggered and segmented in 10 time-stepped phases (0-90%) per cardiac cycle. With identification of the sinotubular junction (STJ), a patient-specific co-ordinate system was created with the z-axis (out-of-plane) parallel to longitudinal direction. The left and right coronary ostia were traced at each time-step to quantify downward motion in reference to the STJ plane, motion within the STJ plane (in-plane), and the degree of rotation. Enrolled individuals had an age of 65 ± 12, and 14 were male (35%). The out-of-plane motion was recorded with the largest displacement of 10.26 ± 2.20 and 8.67 ± 1.69 mm referenced by left and right coronary ostia, respectively. The mean downward movement of aortic root was 9.13 ± 1.86 mm. The largest in-plane motion was recorded at 9.17 ± 2.33 mm and 6.51 ± 1.75 mm referenced by left and right coronary ostia, respectively. The largest STJ in-plane motion was 7.37 ± 1.96 mm, and rotation of the aortic root was 11.8 ± 4.60°. Conclusion: In vivo spatial and temporal displacement of the aortic root can be identified and quantified from multiphase ECG-gated contrast-enhanced CT images. Knowledge of normal 4D motion of the aortic root may help understand its biomechanical impact in patients with aortopathy and pre- and post-surgical or transcatheter aortic valve replacement.

Endomucin marks quiescent long-term multi-lineage repopulating hematopoietic stem cells and is essential for their transendothelial migration.

Endomucin (EMCN) currently represents the only hematopoietic stem cell (HSC) marker expressed by both murine and human HSCs. Here, we report that EMCN+ long-term repopulating HSCs (LT-HSCs; CD150+CD48-LSK) have a higher long-term multi-lineage repopulating capacity compared to EMCN- LT-HSCs. Cell cycle analyses and transcriptional profiling demonstrated that EMCN+ LT-HSCs were more quiescent compared to EMCN- LT-HSCs. Emcn-/- and Emcn+/+ mice displayed comparable steady-state hematopoiesis, as well as frequencies, transcriptional programs, and long-term multi-lineage repopulating capacity of their LT-HSCs. Complementary functional analyses further revealed increased cell cycle entry upon treatment with 5-fluorouracil and reduced granulocyte colony-stimulating factor (GCSF) mobilization of Emcn-/- LT-HSCs, demonstrating that EMCN expression by LT-HSCs associates with quiescence in response to hematopoietic stress and is indispensable for effective LT-HSC mobilization. Transplantation of wild-type bone marrow cells into Emcn-/- or Emcn+/+ recipients demonstrated that EMCN is essential for endothelial cell-dependent maintenance/self-renewal of the LT-HSC pool and sustained blood cell production post-transplant.

Diagnostic measures for monitoring and follow-up in periodontology and implant dentistry.

This review discusses the role of diagnostic measures in the lifelong management of periodontal disease and peri-implant complications. After active treatment, these conditions require regular monitoring of the supporting structures of teeth and dental implants to assess bone and soft tissue health over time. Several clinical measures have been developed for the routine assessment of periodontal and peri-implant tissues, including periodontal and peri-implant probing, bleeding on probing, intraoral radiography, biomarker analysis, and microbiological testing. This review highlights the evolution of diagnostic practices, integrating traditional methods with emerging technologies such as resonance frequency analysis and ultrasound imaging to provide a holistic view of peri-implant health assessment. In addition to objective measurements, patient risk factors are considered. The goals of periodontal and peri-implant maintenance are to control disease activity and stabilize tissues through supportive care, which includes diagnostic measures at follow-up visits. This enables clinicians to monitor treatment outcomes, assess health status, and detect recurrence or progression early through routine evaluation, allowing additional interventions, including adjustment of supportive therapy intervals, to further improve and maintain periodontal and peri-implant stability over time.

The cyanobacterial protein VIPP1 forms ESCRT-III-like structures on lipid bilayers.

The biogenesis and maintenance of thylakoid membranes require vesicle-inducing protein in plastids 1 (VIPP1). VIPP1 is a member of the endosomal sorting complex required for transport-III (ESCRT-III) superfamily, whose members form diverse filament-based supramolecular structures that facilitate membrane deformation and fission. VIPP1 cryo-electron microscopy (EM) structures in solution revealed helical rods and baskets of stacked rings, with amphipathic membrane-binding domains in the lumen. However, how VIPP1 interacts with membranes remains largely unknown. Here, using high-speed atomic force microscopy (HS-AFM), we show that VIPP1 assembles into right-handed chiral spirals and regular polygons on supported lipid bilayers via ESCRT-III-like filament assembly and dynamics. VIPP1 filaments grow clockwise into spirals through polymerization at a ring-shaped central polymerization hub, and into polygons through clockwise polymerization at the sector peripheries. Interestingly, VIPP1 initially forms Archimedean spirals, which upon maturation transform into logarithmic spirals through lateral annealing of strands to the outermore low-curvature spiral turns.

Digital Light 3D Printing of Double Thermoplastics with Customizable Mechanical Properties and Versatile Reprocessability.

Digital light processing (DLP) is a 3D printing technology offering high resolution and speed. Printable materials are commonly based on multifunctional monomers, resulting in the formation of thermosets that usually cannot be reprocessed or recycled. Some efforts are made in DLP 3D printing of thermoplastic materials. However, these materials exhibit limited and poor mechanical properties. Here, a new strategy is presented for DLP 3D printing of thermoplastics based on a sequential construction of two linear polymers with contrasting (stiff and flexible) mechanical properties. The inks consist of two vinyl monomers, which lead to the stiff linear polymer, and α-lipoic acid, which forms the flexible linear polymer via thermal ring-opening polymerization in a second step. By varying the ratio of stiff and flexible linear polymers, the mechanical properties can be tuned with Young's modulus ranging from 1.1 GPa to 0.7 MPa, while the strain at break increased from 4% to 574%. Furthermore, these printed thermoplastics allow for a variety of reprocessability pathways including self-healing, solvent casting, reprinting, and closed-loop recycling of the flexible polymer, contributing to the development of a sustainable materials economy. Last, the potential of the new material in applications ranging from soft robotics to electronics is demonstrated.

Drug administration via feeding tubes-a procedure that carries risks: systematic identification of critical factors based on commonly administered drugs in a cohort of stroke patients.

PURPOSE: Drug administration via feeding tubes is considered a process with many uncertainties. This review aimed to give a comprehensive overview of data available on feeding tube application and to carry out risk assessments for drug substances commonly administered to stroke patients. METHODS: Drugs frequently administered via feeding tubes were identified through a retrospective analysis of discharge letters from a stroke unit. Physicochemical, pharmacokinetic, and stability properties of these drugs and data on drug-enteral nutrition interactions were systematically searched for in the European Pharmacopoeia, Hagers Handbook of Pharmaceutical Practice, Birchers clinical-pharmacological data compilation, and the Martindale Complete Drug Reference, as well as from databases including DrugBank, DrugDex, PubChem, Google Scholar, and PubMed. RESULTS: Of the drugs most commonly administered via feeding tubes in the present stroke patient cohort, bisoprolol, candesartan, and ramipril could be considered the least critical due to their overall favourable properties. Acetylsalicylic acid, amlodipine, hydrochlorothiazide, omeprazole and esomeprazole, simvastatin, and torasemide pose risks based on pH or light-dependent instability or proposed food effects. The most critical drugs to be administered via feeding tubes are considered to be furosemide, levodopa, and levothyroxine as they show relevant instabilities under administration conditions and substantial food effects; the latter two even possess a narrow therapeutic index. However, little information is available on drug-tube and drug-formula interactions. CONCLUSION: Feeding tube administration of medications turned out to be a highly complex process with several unmet risks. Therefore, investigations that systematically assess these risk factors using clinically relevant model systems are urgently needed.

Natural Products Have Increased Rates of Clinical Trial Success throughout the Drug Development Process.

Natural products (NPs) or their derivatives represent a large proportion of drugs that successfully progress through clinical trials to approval. This study explores the presence of NPs in both early- and late-stage drug discovery to determine their success rate, and the factors or features of natural products that contribute to such success. As a proxy for early drug development stages, we analyzed patent applications over several decades, finding a consistent proportion of NP, NP-derived, and synthetic-compound-based patent documents, with the latter group outnumbering NP and NP-derived ones (approximately 77% vs 23%). We next assessed clinical trial data, where we observed a steady increase in NP and NP-derived compounds from clinical trial phases I to III (from approximately 35% in phase I to 45% in phase III), with an inverse trend observed in synthetics (from approximately 65% in phase I to 55% in phase III). Finally, in vitro and in silico toxicity studies revealed that NPs and their derivatives were less toxic alternatives to their synthetic counterparts. These discoveries offer valuable insights for successful NP-based drug development, highlighting the potential benefits of prioritizing NPs and their derivatives as starting points.

Modelling years of life lost due to acute type A aortic dissection in the German healthcare setting: a predictive study.

OBJECTIVES: This study aimed to develop a patient-centred approach to the burden of acute type A aortic dissection (ATAAD) through modelling. The main objective was to identify potential improvements in managing this life-threatening cardiovascular condition and to provide evidence-based recommendations to optimise outcomes. DESIGN: We developed a predictive model along patient pathways to estimate the burden of ATAAD through the years of life lost (YLLs) metric. The model was created based on a systematic review of the literature and was parameterised using demographic data from the German healthcare environment. The model was designed to allow interactive simulation of different scenarios resulting from changes in key impact factors. SETTING: The study was conducted using data from the German healthcare environment and results from the literature review. PARTICIPANTS: The study included a comprehensive modelling of ATAAD cases in Germany but did not directly involve participants. INTERVENTIONS: There were no specific interventions applied in this study based on the modelling design. PRIMARY AND SECONDARY OUTCOME MEASURES: The single outcome measure was the estimation of YLL due to ATAAD in Germany. RESULTS: Our model estimated 102 791 YLL per year for ATAAD in Germany, with 62 432 and 40 359 YLL for men and women, respectively. Modelling an improved care setting yielded 93 191 YLL or 9.3% less YLL compared with the current standard while a worst-case scenario resulted in 113 023 or 10.0% more YLL. The model is accessible at https://acuteaorticdissection.com/ to estimate custom scenarios. CONCLUSIONS: Our study provides an evidence-based approach to estimating the burden of ATAAD and identifying potential improvements in the management of pathways. This approach can be used by healthcare decision-makers to inform policy changes aimed at optimising patient outcomes. By considering patient-centred approaches in any healthcare environment, the model has the potential to improve efficient care for patients suffering from ATAAD.

Piximi - An Images to Discovery web tool for bioimages and beyond.

Deep learning has greatly accelerated research in biological image analysis yet it often requires programming skills and specialized tool installation. Here we present Piximi, a modern, no-programming image analysis tool leveraging deep learning. Implemented as a web application at Piximi.app, Piximi requires no installation and can be accessed by any modern web browser. Its client-only architecture preserves the security of researcher data by running all computation locally. Piximi offers four core modules: a deep learning classifier, an image annotator, measurement modules, and pre-trained deep learning segmentation modules. Piximi is interoperable with existing tools and workflows by supporting import and export of common data and model formats. The intuitive researcher interface and easy access to Piximi allows biological researchers to obtain insights into images within just a few minutes. Piximi aims to bring deep learning-powered image analysis to a broader community by eliminating barriers to entry.

The lipopeptide Pam3CSK4 inhibits Rift Valley fever virus infection and protects from encephalitis.

Rift Valley fever virus (RVFV) is an encephalitic bunyavirus that can infect neurons in the brain. There are no approved therapeutics that can protect from RVFV encephalitis. Innate immunity, the first line of defense against infection, canonically antagonizes viruses through interferon signaling. We found that interferons did not efficiently protect primary cortical neurons from RVFV, unlike other cell types. To identify alternative neuronal antiviral pathways, we screened innate immune ligands and discovered that the TLR2 ligand Pam3CSK4 inhibited RVFV infection, and other bunyaviruses. Mechanistically, we found that Pam3CSK4 blocks viral fusion, independent of TLR2. In a mouse model of RVFV encephalitis, Pam3CSK4 treatment protected animals from infection and mortality. Overall, Pam3CSK4 is a bunyavirus fusion inhibitor active in primary neurons and the brain, representing a new approach toward the development of treatments for encephalitic bunyavirus infections.

Is surgical quality more important than radicality? Long-term outcomes of stage I-III colon cancer (SAKK 40/00).

BACKGROUND: To prospectively determine the influence of variations of surgical radicality and surgical quality on long-term outcome in patients with stage I-III colon cancer. METHODS: From a prospective multicenter cohort study including 1040 patients undergoing surgery for colorectal cancer from 09/2001 to 06/2005 in nine Swiss and one German hospital, 423 patients with stage I-III colon cancer were selected and analyzed. Surgeons and pathologists filled in standardized forms prospectively assessing items of oncosurgical radicality and quality. Patients had standardized follow-up according to national guidelines. RESULTS: Follow-up was median 6.2 years (range 0.3-10.4) showing a 5-year disease-free survival/overall survival of 83 %/87 % in stage I (n = 85), 69 %/77 % in stage II (n = 187), and 53 %/61 % in stage III (n = 151) colon cancer. Despite remarkable variations of oncosurgical radicality and quality, the multivariate model revealed that mainly quality items correlated significantly with disease-free survival (surgical tumor lesion HR 2.12, p = 0.036, perioperative blood transfusion HR 1.67, p = 0.018, emergency resection HR 1.74, p = 0.035) and overall survival (early venous ligation HR 0.66, p = 0.023, surgical tumor lesion HR 2.28, p = 0.027, perioperative blood transfusion HR1.79, p = 0.010, emergency resection HR 1.88, p = 0.026), while radicality parameters (length of specimen, distance of the tumor to nearest bowel resection site, number of lymph nodes, height of resected mesocolon and of central vascular dissection) did not. CONCLUSION: Surgical quality seems to have a stronger impact on oncologic long-term outcome in stage I - III colon cancer than surgical radicality.

Investigation of real-life drug intake behaviour in older adults and geriatric patients in Northern Germany - A biopharmaceutical perspective.

Dosing conditions (type and amount of accompanying fluid, the type of food, the time of administration, and dosage form modifications such as crushing tablets) are critical and affect the performance of oral dosage forms in the gastrointestinal tract and thus bioavailability. Because older adults are the primary users of medications and are more susceptible to adverse effects, it is important to understand how they take their medications in order to reduce risks and increase benefits of the pharmacotherapy. The aim of the study was to investigate the real-life drug intake behaviour in geriatric patients and older adults and discuss their influence on drug absorption after oral administration. The data from two settings home vs. hospital and genders women vs. men were presented. A questionnaire study was performed among people aged at least 65 years from two settings (hospital vs. home), recruited mostly from community pharmacies and a regional hospital in Mecklenburg - Western Pomerania. The obtained data demonstrates that older adults and geriatric patients take their medications in the same way regardless of the setting and gender. There were no significant differences. Interviewed participants were mostly adherent to the doctor's recommendations and mostly took their medications in the same way every day. Medications are most commonly taken with a small (100 mL) or large (200 mL) glass of noncarbonated water, after food (during or after breakfast 64 % of intakes in the morning and during or after dinner 81 % of intakes in the evening). Meal usually consisted of bread, either with jam or honey (breakfast), or ham and cheese (dinner). All reported dosage form modifications were made to tablets. In almost all cases it was splitting the tablet, which was performed due to doctor's indication.

The evolutionarily ancient FOXA transcription factors shape the murine gut microbiome via control of epithelial glycosylation.

Evolutionary adaptation of multicellular organisms to a closed gut created an internal microbiome differing from that of the environment. Although the composition of the gut microbiome is impacted by diet and disease state, we hypothesized that vertebrates promote colonization by commensal bacteria through shaping of the apical surface of the intestinal epithelium. Here, we determine that the evolutionarily ancient FOXA transcription factors control the composition of the gut microbiome by establishing favorable glycosylation on the colonic epithelial surface. FOXA proteins bind to regulatory elements of a network of glycosylation enzymes, which become deregulated when Foxa1 and Foxa2 are deleted from the intestinal epithelium. As a direct consequence, microbial composition shifts dramatically, and spontaneous inflammatory bowel disease ensues. Microbiome dysbiosis was quickly reversed upon fecal transplant into wild-type mice, establishing a dominant role for the host epithelium, in part mediated by FOXA factors, in controlling symbiosis in the vertebrate holobiont.

Identifying priority sites for whale shark ship collision management globally.

The expansion of the world's merchant fleet poses a great threat to the ocean's biodiversity. Collisions between ships and marine megafauna can have population-level consequences for vulnerable species. The Endangered whale shark (Rhincodon typus) shares a circumglobal distribution with this expanding fleet and tracking of movement pathways has shown that large vessel collisions pose a major threat to the species. However, it is not yet known whether they are also at risk within aggregation sites, where up to 400 individuals can gather to feed on seasonal bursts of planktonic productivity. These "constellation" sites are of significant ecological, socio-economic and cultural value. Here, through expert elicitation, we gathered information from most known constellation sites for this species across the world (>50 constellations and >13,000 individual whale sharks). We defined the spatial boundaries of these sites and their overlap with shipping traffic. Sites were then ranked based on relative levels of potential collision danger posed to whale sharks in the area. Our results showed that researchers and resource managers may underestimate the threat posed by large ship collisions due to a lack of direct evidence, such as injuries or witness accounts, which are available for other, sub-lethal threat categories. We found that constellations in the Arabian Sea and adjacent waters, the Gulf of Mexico, the Gulf of California, and Southeast and East Asia, had the greatest level of collision threat. We also identified 39 sites where peaks in shipping activity coincided with peak seasonal occurrences of whale sharks, sometimes across several months. Simulated collision mitigation options estimated potentially minimal impact to industry, as most whale shark core habitat areas were small. Given the threat posed by vessel collisions, a coordinated, multi-national approach to mitigation is needed within priority whale shark habitats to ensure collision protection for the species.

Contemporary educational methods in periodontology.

AIM: The 1st European Workshop on Periodontal Education in 2009 made recommendations regarding the scope of periodontal education at undergraduate (UG), postgraduate (PG) and continuing professional development (CPD) levels, defining competencies and learning outcomes that were instrumental at the time in helping to define periodontal teaching curricula. The 19th European Workshop on Periodontology and 2nd European Consensus Workshop on Education in Periodontology (Education in Periodontology in Europe) was held in 2023 to identify changes and future developments in periodontal education (including those informed by the COVID-19 pandemic) and embracing methods and formats of periodontal teaching and training. The aim of this review was to assess current knowledge regarding education methods in periodontology, including traditional face-to-face (F2F) teaching and the move to student-centred methods, virtual learning methods and use of digital technology, as well as blended teaching and learning (including teaching delivery and assessment) at UG, PG and CPD levels. MATERIALS AND METHODS: Systematic searches were conducted to identify relevant studies from the literature. Data were extracted and descriptive summaries collated. RESULTS: The pandemic was a major disruptor of traditional F2F teaching but provided opportunities for rapid implementation of alternative and supplementary teaching methods. Although online learning has become an integral part of periodontal education, teachers and learners alike favour some form of F2F teaching. Blended teaching and learning are feasible in many areas of periodontal education, both for knowledge and skills acquisition as well as in assessment. Student-centred methods and blended approaches such as the flipped classroom seem highly effective, and online/virtual classrooms with both synchronous and asynchronous lectures are highly valued. Learning with haptic methods and virtual reality (VR) enhances the educational experience, especially when VR is integrated with traditional methods. The quality of the teacher continues to be decisive for the best knowledge transfer in all its forms. CONCLUSIONS: Live F2F teaching continues to be highly trusted; however, all types of student-centred and interactive forms of knowledge transfer are embraced as enhancements. While digital methods offer innovation in education, blended approaches integrating both virtual and traditional methods appear optimal to maximize the achievement of learning outcomes. All areas of periodontal education (UG, PG and CPD) can benefit from such approaches; however, more research is needed to evaluate their benefits, both for knowledge transfer and skills development, as well as in assessment.

The elephant's Achilles' heel: a case report of acute obstruction of frozen elephant trunk after proximal aortic dissection repair.

Background: The frozen elephant trunk (FET) technique as a hybrid combining surgical and endovascular repair is an emerging concept to treat complex aortic dissection. Early experience showed technical feasibility and promising clinical outcomes. However, unsuspected complications still arise. Case summary: A 25-year-old male presented to the emergency department with a 2-day history of chest pain. After exclusion of acute coronary syndrome, a computed tomography angiography (CTA) revealed Type A (DeBakey Type I) aortic dissection. The patient underwent median stenotomy for complete replacement of the ascending aorta, the aortic arch, and FET. Early after rewarming, the patient became unstable due to severe left ventricular dysfunction. Soon veno-arterial extracorporal membrane oxygenation (VA-ECMO) was required for circulatory support. The cause of deterioration remained unclear until repeated CTA showed acute obstruction of the FET. Invasive exploration confirmed a trans-FET gradient of 100 mmHg, successfully managed by repeated balloon inflation with resolution of both obstruction and gradient. The patient recovered completely without any sequela. Discussion: While the mechanism of acute obstruction after FET remains subject to speculation, the rescue intervention of ballooning the obliteration on VA-ECMO was life-saving. Intraoperative ultrasound and videoscopic inspection may be instrumental before chest closure to avoid such critical events.