Coronary collaterals are vascular connections that bridge epicardial arteries and supply blood to the oxygen-deprived myocardium in patients with coronary artery disease (CAD). This comprehensive review aimed to identify and evaluate potential interventions that may enhance the growth of coronary collateral vessels. We conducted a scoping review of five databases to identify relevant studies that focused on interventions that may promote coronary collateral circulation in patients with CAD. Our search identified 23 studies that met our inclusion criteria. Studies (n=7) using pharmacologic agents (i.e., angiotensin-converting enzyme inhibitors, granulocyte macrophage colony stimulating factor, statins, human recombinant basic fibroblast growth factor, and granulocyte macrophage colony stimulating factor) were found to improve collateralization, as did the non-pharmacologic studies (n=13) (i.e., exercise training, electrical stimulation, and enhanced external counter pulsation), which formed most of the studies. Three studies found benefits of a combination of exercise and heparin. Improvements were seen in collateralization as measured by the coronary flow index and Rentrop scores across all interventions. Effect sizes from randomized trials with pharmacologic, non-pharmacologic, and exercise-based interventions ranged between 0.4-0.7. This review provides a comprehensive overview and update of the existing literature on interventions that may promote coronary collateralization (CC). In summary, we observed a few pharmacological and non-pharmacological (exercise, electrical stimulation, and enhanced external counter pulsation) interventions that have shown a positive effect on CC. These data provide a framework for more robust trials regarding the proliferation and clinical significance of enhanced CC in cardiovascular outcomes in patients with known or occult CAD.
Xenosurveillance, which uses blood-feeding insects as biological samplers, is an emerging non-invasive approach for monitoring pathogens circulating among humans, livestock, and wildlife. However, its application to livestock-associated bacterial pathogens at human-animal-wildlife interfaces remains underexplored. We investigated whether mosquito blood meals could be used to detect tick-borne bacterial pathogens circulating in livestock in Kenya. We collected 4673 mosquitoes, belonging to Culex, Anopheles, Aedes, Mansonia, and Coquillettidia genera around livestock enclosures in Kajiado and Naivasha counties, Kenya, using CO₂-baited CDC miniature light traps. Traps were selected to maximise species diversity, and as light traps capture fewer engorged mosquitoes than resting traps, only 56 blood-fed individuals (1.2%) were collected and processed as whole-specimen homogenates and analysed for vertebrate blood-meal sources using cytochrome b sequencing. In total, 303 mosquito pools, including blood-fed individuals processed as single-mosquito pools, were screened for Anaplasma, Ehrlichia, Rickettsia, Theileria, and Babesia using PCR-high-resolution melting analysis and confirmatory sequencing. All pathogen-positive detections were exclusively from blood-fed individuals. We detected Anaplasma marginale in Culex pipiens (1/150; 0.7%) and Aedes hirsutus (2/11; 18.2%), Anaplasma sp. in Cx. pipiens (2/150; 1.4%) and Ae. hirsutus (1/11; 9.1%), and Candidatus Neoehrlichia mikurensis in Mansonia africana (2/50; 4%). Pathogen detections showed strong host concordance, where A. marginale was associated with cattle-derived blood meals and Anaplasma sp. with goat-derived blood meals, while Candidatus Neoehrlichia mikurensis was detected in Mn. africana that had fed on cattle and on a host that could not be determined. Our results provide preliminary evidence that mosquito-based xenosurveillance can detect tick-borne bacterial pathogens circulating in livestock at human-wildlife interfaces in Kenya. The strong concordance between pathogen identity and vertebrate host in blood-fed mosquitoes supports the biological plausibility of this approach. Notably, detection of Ca. Neoehrlichia mikurensis represents the first report of this zoonotic pathogen in mosquitoes in Africa, highlighting the One Health relevance of xenosurveillance in identifying settings, where pathogen circulation and cross-interface feeding coincide. Mosquito-derived sampling has potential to complement existing surveillance tools in agro-pastoral systems, where direct host sampling is difficult or costly.
Wastewater surveillance has proved to be a valuable tool for monitoring human pathogens. Whole-genome sequencing of SARS-CoV-2 in wastewater has been extensively applied, allowing for early detection of variants and population-level surveillance of viral diversity and abundance; however, limited studies have applied this methodology to influenza. Here, we investigated influenza A and B diversity year-round in five metropolitan areas and one major international airport in Germany during 2024 using wastewater-based whole-genome sequencing. We applied amplicon-based sequencing covering all eight genome segments of both influenza A and B to 401 wastewater samples, yielding 339 influenza-positive samples. Bioinformatic analysis classified sequencing data, enabling subtype assignment and segment-level assessment of circulating influenza diversity. We recovered partial to near-complete genomes for influenza A and B for many influenza-positive samples. The results largely paralleled clinical subtype patterns across Germany, with winter peaks of H1N1 and small proportions of influenza B. In contrast, airport samples showed persistent off-season detection, a higher baseline of read counts across the entire year, and a greater proportion of H3N2 and influenza B reads. Segment-level characterization also revealed low-abundance reads assigned to several avian influenza subtypes, including H5N1, which were not clinically reported. These findings demonstrate the utility of wastewater whole-genome sequencing for population-level influenza surveillance. Distinct seasonal and off-season patterns highlight the value of year-round monitoring at international airports and seasonal monitoring in municipal systems, providing a framework to guide future influenza wastewater surveillance strategies.
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis characterized by eosinophilic inflammation and potential cardiovascular involvement. The relationship between eosinophil burden and subclinical cardiopulmonary vascular dysfunction remains unclear. 27 EGPA patients were evaluated. Peripheral eosinophil counts (PEC) at diagnosis were analysed in relation to echocardiographic markers of pulmonary vascular load and right ventricular-pulmonary artery (RV-PA) coupling. Patients initiating anti-IL-5/R therapy (mepolizumab or benralizumab) underwent echocardiography assessing pulmonary artery systolic pressure (PAPs), tricuspid annular plane systolic excursion (TAPSE), TAPSE/PAPs ratio, and tricuspid regurgitation velocity (TRV) at diagnosis, treatment initiation (Baseline), and 24-month follow-up (T24) to assess temporal changes. Patients were stratified by median PEC. Multivariable regression and ROC analyses were performed. At Baseline, 33% of patients exhibited elevated PAPs (>25 mmHg) despite absence of clinical pulmonary hypertension. Higher PEC were associated with increased PAPs (p = 0.04) and reduced TAPSE/PAPs ratio (p = 0.03). Pulmonary vascular load worsened from diagnosis to T0 and improved after anti-IL-5/R therapy, with PAPs decreasing from 27.5 [18.0-30.0] mmHg to 18.0 [11.75-20.0] mmHg (p = 0.002) and TRV from 2.30 [1.65-2.48] to 1.80 [1.28-1.92] m/s (p = 0.005). Baseline PEC moderately discriminated patients with intermediate/high echocardiographic probability of pulmonary hypertension (AUC 0.751). Elevated PEC may signal early pulmonary vascular dysfunction and RV-PA uncoupling EGPA, which may be partially reverted with anti-IL-5/R therapy. These findings support the importance of early cardiovascular surveillance in eosinophil-rich EGPA.
Hydrocarbon contaminants in soil exhibit long-term persistence in low-permeability zones, where their low solubility and limited mobility make remediation challenging. Electrokinetic techniques provide a promising solution by enhancing surfactant delivery in low-permeability media through electroosmosis and electromigration. However, the role of heterogeneity remains poorly understood, arising not only from permeability differences that govern Darcy flow but also from variations in zeta potential that control electroosmotic flow. This study investigates how two-dimensional heterogeneity influences water flow, surfactant transport, and hydrocarbon removal under electrokinetic conditions. Laboratory experiments were carried out using heterogeneous soil-sand systems, with nonionic surfactants applied to enhance hydrocarbon solubility and mobility. Numerical models were developed to simulate water flow, surfactant transport, and hydrocarbon removal. In two-dimensional heterogeneous systems, distinct transport and removal behaviors were observed between electrokinetic and hydraulic gradient methods. Localized circulation flow around the soil block was observed and can be generated either by an externally imposed hydraulic gradient between the anode and cathode or by the intrinsic heterogeneity of the system, particularly the differences in hydraulic conductivity and zeta potential between soil and sand. This circulation, produced by the competition between electroosmotic pumping in high-zeta potential soils and Darcy flow in sand near the sand-soil interface, reduces surfactant delivery and limits hydrocarbon removal. Finally, a combined electrokinetic-hydraulic gradient method is proposed and demonstrated to enhance removal efficiency, offering a promising approach for field applications in heterogeneous media.
Understanding when ice sheets first developed over the continents is essential for attributing ice volume to marine records of global sea-level change. We resolve a long-standing terrestrial-marine mismatch in the timing of the first Eurasian Ice Sheet (EIS) expansion by dating the earliest glaciogenic unit in northwest Europe, the Hattem Bed Complex (HBC). Paired cosmogenic 26Al-10Be burial dating and detrital zircon fingerprinting indicate that glacially-derived Fennoscandian gravels reached the Netherlands 2.41-0.29+0.51 Ma, while ages from the overlying Appelscha Formation record a second EIS advance and attendant shutdown of the Baltic River System 1.72-0.25+0.25 Ma. Cyclic stratification of the HBC could reflect freshwater discharge to the North Atlantic associated with episodic disruption of meridional overturning circulation. The timing of the first trans-Baltic EIS overlaps the Laurentide Ice Sheet maximum (2.42-0.14+0.14Ma), underscoring substantial Northern Hemisphere ice growth more than a million years prior to the Mid-Pleistocene Transition.
In times when health and physical activity are gaining in value, the search for effective methods to support fitness and improve quality of life is becoming a priority. One of the therapies that is gaining increasing popularity is pressotherapy, which supports the regeneration of the body on many levels. The study was conducted on a group of 15 healthy, young women. The participants underwent 10 pneumatic compression therapy treatments using the CarePump Expert8 device. The participants were examined 4 times: a week before the first treatment, immediately before the first treatment, after the 10th treatment and a week after the 10th treatment. Statistical analysis of mean changes in the range of motion values showed significant decrease in: right (p < 0.05) and left (p < 0.05) hip joint extension; right (p < 0.05) hip joint horizontal abduction; horizontal adduction of the right (p < 0.05) and left (p < 0.05) hip joint; dorsiflexion of the right (p < 0.05) and left (p < 0.05) ankle joint, and also an increase in: right (p < 0.05) and left (p < 0.05) hip external rotation. Statistical analysis of changes in mean values of circumferences showed significant decrease at all tested levels: P1 right (p < 0.05) and left (p < 0.05); U1 right (p < 0.05) and left (p < 0.05); U2 right (p < 0.05) and left (p < 0.05); K right (p < 0.05) and left (p < 0.05); G1 right (p < 0.05); and left (p < 0.05); G2 right (p < 0.05) and left (p < 0.05). A series of pressotherapy sessions did not improve lower limb range of motion or body composition indices; however, it did reduce circumferences at all levels of the lower limbs. Long-term use of pressotherapy can help maintain healthy fluid levels, improve circulation, and improve overall physical fitness.
Recent reclassification of steatotic liver disease (SLD) distinguishes metabolic dysfunction-associated steatotic liver disease (MASLD) from MetALD, a newly defined entity combining MASLD with alcohol consumption. Since the mechanisms linking alcohol consumption in the context of SLD to cardiovascular disease (CVD), the leading cause of SLD mortality, remain elusive, we investigated how metabolic dysregulation and alcohol intake synergistically promote atherosclerosis. Low-density lipoprotein receptor-deficient (Ldlr-/-) mice were fed a high-fat, high-cholesterol (HFC) diet with regular or ethanol-containing drinking water (10-20% v/v). Germ-free and antibiotic-treated Ldlr-/- mice were used to assess the contribution of ethanol-induced dysbiosis. Associations between alcohol consumption and cardiometabolic risk were assessed in two human cohorts (N = 5115, N = 2515). Ethanol intake in HFC diet-fed Ldlr-/- mice exacerbated hepatic steatosis and systemic dyslipidemia, despite only modest elevations in systemic ethanol levels (ps≤0.05). Liver transcriptomic profiling revealed ethanol-induced alterations in lipid metabolism and enhanced proinflammatory signatures, accompanied by increased recruitment of Ly6Chigh monocytes to the liver (p=0.0121) and elevated levels in circulation (p=0.0043). Correspondingly, ethanol-consuming HFC diet-fed Ldlr-/- mice developed enlarged aortic root lesions (p=0.0105). Neither germ-free conditions nor antibiotic treatment mitigated CVD progression. Metabolomic profiling revealed hyperuricemia in ethanol-exposed HFC diet-fed Ldlr-/- mice, which was associated with an upregulation of inflammasome-related genes in the liver, along with an increase in hepatic NLRP3 protein expression (ps≤0.05). Notably, human data mirrored these findings, demonstrating a dose-dependent association between alcohol intake, dyslipidemia, monocytosis, hyperuricemia, and increased cardiovascular risk (ps≤0.05). Our findings identify alcohol as an important immune-modulatory lifestyle factor that contributes to elevated cardiovascular risk. Alcohol consumption, even at moderate levels, contributes to cardiovascular risk, particularly in individuals with SLD. Combining murine models with human cohort data, we show that alcohol intake in SLD is associated with coordinated immune-metabolic alterations, including dyslipidemia, monocytosis, hyperuricemia, and enhanced NLRP3 inflammasome signaling, collectively indicating an elevated cardiovascular risk profile. These findings are relevant to hepatology and cardiovascular medicine, linking alcohol consumption to measurable systemic pathways beyond liver injury. Clinically, systematic assessment of alcohol intake and incorporation into cardiovascular risk evaluation may improve risk stratification and support closer surveillance and preventive strategies in patients with SLD.
Gut bacterial β-glucuronidase (GUS) is essential for enterohepatic circulation, by reactivating drug metabolites within the intestine and exerting toxicological effects. GUS inhibitors have shown great clinical potential for the alleviation of drug-induced intestinal toxicity. To discover and characterize natural GUS inhibitors from traditional Chinese medicine (TCM) for the prevention and treatment of irinotecan-induced intestinal toxicity. A fluorescence-based screening platform was established to evaluate GUS inhibitors from TCM. A mouse model of irinotecan-induced intestinal toxicity was developed to assess the therapeutic efficacy of Arnebia euchroma (Royle ex Benth.) I.M.Johnst. (Zicao). Bioactive compounds were isolated and purified from Zicao using a preparative high-pressure liquid chromatography (HPLC) instrument. In addition, enzyme kinetics, molecular docking, and molecular dynamics simulations were employed to elucidate specific inhibitory mechanisms. Zicao exhibited potent GUS inhibitory activity, reversed irinotecan-induced GUS elevation, and relieved irinotecan-induced intestinal toxicity in mice. Phytochemical investigation identified 28 compounds from Zicao, including seven potent GUS inhibitors: shikonofurans (A, E, F, and J) and arnebinols (A, B, and C). Shikonofuran A acted as a non-competitive inhibitor by bonding to the amino acid residues Tyr397, Gln396, and Asn444 of GUS and exhibited direct anti-inflammatory effects by suppressing LPS-induced cytokine secretion in mouse macrophages. Zicao alleviated irinotecan-induced intestinal toxicity via potent GUS inhibition. Shikonofurans (A, E, F, J) and arnebinols (A, B, C) were identified and characterized as responsible for the inhibitory effect of Zicao on GUS. Zicao and its derivatives may serve as adjuvant therapeutics for mitigating irinotecan-induced intestinal toxicity in the clinic.
Bone is among the most apoptotically active tissues in the body. During remodeling, repair, and disease, dying osteoclasts, osteoblast-lineage cells, osteocytes, mesenchymal stem/stromal cells, and injury-associated cells release apoptotic bodies (ABs) that retain parent-cell-derived cargo and surface ligands. These vesicles are increasingly viewed not only as debris for efferocytic clearance but also as source-specific signalling units that shape skeletal cell fate, immune activity, mineralization, and repair. This review integrates current evidence for ABs across skeletal homeostasis and disease. We first define ABs within the broader extracellular vesicle landscape, emphasizing vesicle heterogeneity, isolation and characterization challenges, and terminology boundaries. We then examine AB sources and recipient interfaces, including osteoclasts, osteoblast-lineage cells, osteocytes, mesenchymal stem/stromal cells, platelet-derived ABs in injury repair, macrophages, osteoclast phagocytes, chondrocytes, and bone lining cells. We further discuss how dysregulated AB signalling contributes to osteoporosis, osteoarthritis, and bone metastasis, as well as alveolar bone destruction, aging-related bone loss, osteochondral mineralization, and bone injury repair. We highlight therapeutic implications, including AB-based or AB-inspired strategies, the cathepsin K (CTSK)-responsive self-assembling peptide nanoparticle OsteoSAVE for in vivo generation of osteoclast-derived ABs, and the hypothesis that antiresorptive therapies may reshape osteoclast-derived AB (OC-AB) production. We also identify unresolved translational questions, including AB lifespan, circulation, source attribution, and direct human validation.
Cardiovascular diseases (CVDs) continue to be a significant public health burden and public health emergency in the world, underscoring the importance of early and easily accessible cardiovascular risk prediction strategies. While systemic clinical and biochemical markers have been the mainstay of traditional risk assessment models, there is growing evidence that microvascular dysfunction is an early marker of vascular injury that is present prior to the onset of overt cardiovascular disease. The retinal microvasculature offers a unique non-invasive window into systemic vascular health, given its structural and physiological similarities with the coronary and cerebral circulation. Microvascular retinal changes such as changes in vascular caliber, tortuosity, branching and patterns of perfusion, are associated with hypertension, diabetes mellitus, stroke, coronary artery disease and heart failure. Advanced retinal imaging techniques like optical coherence tomography angiography (OCT-A) also allow to analyse the architecture of retinal vessels and microcirculatory function in detail. In addition, emerging molecular evidence shows shared pathways of endothelial dysfunction, inflammation, oxidative stress, and activation of the renin-angiotensin system, that link retinal vascular remodeling to cardiovascular pathology. Over the past few years, the use of artificial intelligence (AI) and deep learning (DL) has dramatically increased the capability of retinal imaging for translation, leading to automated acquisition of high dimensional vascular features and prediction of cardiovascular risk from retinal photographs. Retinal imaging biomarkers could complement clinical and molecular parameters to enhance risk stratification for cardiovascular disease in an individual basis. Overall, retinal microvascular phenotyping is a promising tool for early cardiovascular risk assessment, scalable, and non-invasive, and could play a role in future precision cardiology and preventive cardiovascular care strategies.
Measles is a highly contagious infectious disease and remains a major cause of global morbidity and mortality. Molecular surveillance of measles virus (MV) is used for tracing transmission chains, by, for instance, distinguishing between repeated introductions and endemic circulation. WHO guidelines used in the global measles surveillance network recommend sequencing of a 450-nucleotide region at the C-terminal end of the N-gene (N450). Given the limited genetic variability of MV, whole-genome sequencing would increase the resolution and provide a more detailed molecular surveillance of circulating MV. In this study, we describe an amplicon-based nanopore sequencing protocol for generating near complete whole MV genome sequences (nWGS; 15,813 nucleotides). We applied this protocol to samples collected during an epidemic of measles in the Netherlands in 2013-2014, involving an estimated 30,000 cases, to quantify the sequence variation of nWGS during this epidemic. While this was considered an epidemic with very limited sequence variation based on analysis of the N450 region, different molecular clusters were identified by phylogenetic analysis of nWGS genomes. Notably, the number of single nucleotide variants (SNVs) between viruses detected during the early and late phase of the epidemic varied among molecular clusters. Four epidemiological clusters could be identified in the beginning of the epidemic, of which 2 were supported by molecular data. Analysis of nWGS genomes suggested that the epidemic started with either a single unnoticed introduction into the Netherlands and a few unnoticed generations or with at least 2 introductions at the same time, the latter option is supported by epidemiological data. These results can aid in interpreting MV sequence variation during transmission chains, outbreaks and epidemics in countries or regions approaching measles elimination.
Extracorporeal life support provides temporary cardiorespiratory support for patients with severe, potentially reversible cardiac and/or respiratory failure refractory to conventional measures. Its application has broadened across a wide spectrum of critical illness, yet the mechanistic basis of its physiological benefit remains incompletely defined.This review explores the mechanisms through which extracorporeal life support may confer benefit in respiratory and cardiac failure. These include restoration of gas exchange, optimization of circulatory dynamics, and mitigation of secondary organ injuries, creating conditions that facilitate tissue repair, enable adjunctive therapies, and in selected cases, provide a bridge to transplantation. In isolated respiratory failure, respiratory extracorporeal life support stabilizes gas exchange and modulates respiratory drive, enabling lung-protective ventilation and potentially attenuating ventilator- and patient self-inflicted lung injury. In cardiogenic shock, cardiac extracorporeal life support restores systemic perfusion and may reduce myocardial oxygen demand, while during cardiac arrest it may confer neuro-protective effects. In combined cardiorespiratory failure, advanced extracorporeal support modalities may augment both systemic and pulmonary circulation, supporting gas exchange and maintaining end-organ perfusion. Mechanistically, these interventions interrupt the cascade of hypoxemia- and/or hypercapnia- induced pulmonary vasoconstriction, right ventricular overload, and systemic hypoperfusion, facilitating multi-organ recovery. Optimizing patient selection, timing for extracorporeal life support initiation, and use of adjunctive therapies require a nuanced understanding of the interplay between these physiological pathways alongside careful considerations of key limitations including device-related complications, hematologic and inflammatory perturbations, and physiological trade-offs. This concise clinical review synthesizes the current literature on the mechanistic basis of extracorporeal life support in adults.
All climate models project that the Atlantic Meridional Overturning Circulation (AMOC) will weaken in the 21st century, but most models neglect increasing runoff from the Greenland ice sheet. Greenland meltwater is expected to exacerbate AMOC weakening, and omitting it increases the uncertainty in assessing the possibility of an abrupt AMOC collapse or tipping. Here, we test the abruptness and reversibility of AMOC changes under strong future global warming in a state-of-the-art climate model with and without high-end but physically plausible Greenland meltwater forcing. In this model, Greenland meltwater significantly exacerbates future AMOC weakening especially after 2100, but the AMOC changes until 2300 are neither abrupt nor irreversible on centennial timescales, even with added meltwater. While accounting for Greenland meltwater will increase the accuracy of climate projections, our results do not suggest a major role of Greenland meltwater for assessing the risk of future AMOC tipping.
Patients with a patent foramen ovale (PFO) have an increased risk of perioperative cerebral stroke due to the potential for paradoxical embolism. It is pathophysiologically plausible that this risk is further increased when bone cement implantation syndrome (BCIS) occurs during endoprosthetic joint surgery; however, despite double-digit prevalence rates for both PFO and BCIS, the perioperative concurrence of these conditions with subsequent paradoxical embolism has not previously been reported.We describe an 81-year-old woman with a known PFO who developed intraoperative BCIS during cemented hip arthroplasty and subsequently sustained a paradoxical embolic stroke involving a large cerebral vessel. The potential pathophysiological links between PFO and BCIS are discussed, and anesthesiological implications and practical recommendations are derived from the current literature.Published estimates of paradoxical embolism risk during endoprosthetic joint replacement are highly inconsistent, ranging from no increased risk to a 29-fold increase. This variability may partly reflect that many embolic events remain clinically silent.For paradoxical embolism two conditions are required: (1) gaseous or particulate emboli must enter the venous circulation and (2) the physiological left-to-right interatrial shunt must reverse to a right-to-left shunt through the PFO. Both mechanisms can be promoted by BCIS by generating embolic load from the surgical field and increasing pulmonary vascular resistance, thereby favoring right-to-left shunting. Because specific anesthesiological preventive and therapeutic options are limited, close postoperative monitoring is essential and any new neurological or hemodynamic abnormalities should prompt immediate comprehensive diagnostic evaluation. Patienten mit einem offenen Foramen ovale (PFO) haben wegen der Gefahr einer paradoxen Embolie ein erhöhtes Risiko für einen perioperativen cerebralen Insult. Es erscheint pathophysiologisch plausibel, dass dieses Risiko durch Auftreten einer Knochenzementreaktion („bone cement implantation syndrome“, BCIS) bei endoprothetischen Gelenkoperationen weiter zunimmt. Aber trotz einer PFO- bzw. BCIS-Inzidenz im jeweils zweistelligen Prozentbereich gibt es bisher keine Berichte über die mögliche Koinzidenz beider Komplikationen.Am Beispiel einer 81-jährigen PFO-Trägerin, die während einer Hüfttotalendoprothese (Hüft-TEP) ein BCIS erlitt und sich in der Folge eine paradoxe Embolie mit zerebralem Insult entwickelte, werden die pathophysiologischen Interaktionen beider Krankheitsbilder aufgezeigt. Anhand der aktuellen Literatur werden die daraus folgenden anästhesiologischen Implikationen diskutiert und Empfehlungen abgeleitet.Die Wahrscheinlichkeit einer paradoxen Embolie bei endoprothetischem Gelenkersatz wird im Schrifttum mit großer Inkohärenz angegeben, von 0 % bis zu einem um den Faktor 29 gesteigerten Risiko. Diese schwer vereinbarenden Befunde lassen sich dadurch erklären, dass nicht alle stattfindenden Embolien auch klinisch sichtbar werden.Für eine paradoxe Embolie sind zwei Voraussetzungen notwendig: Im venösen Gefäßsystem müssen gasförmige oder korpuskuläre Emboli vorhanden sein, und es muss es zu einer Umkehr des physiologischen transforaminalen Links(L)/Rechts(R)-Shunts zu einem pathologischen R/L-Shunt kommen. Beide Mechanismen werden durch ein BCIS induziert, im Operationsgebiet werden Emboli freigesetzt und durch einen Anstieg des pulmonalvaskulären Widerstands (PVR) entsteht ein R/L-Shunt. Die Gefahr einer paradoxen Embolie nimmt zu. Die anästhesiologischen prophylaktischen und therapeutischen Möglichkeiten zur Intervention sind begrenzt. Bei postoperativen neurologischen oder hämodynamischen Auffälligkeiten ist deshalb eine sofortige umfassende Diagnostik zur Abklärung unverzichtbar.
Usutu virus (USUV) is a medically important flavivirus linked to significant mortalities within bird populations and an increasing association with human infections, particularly within immunocompromised individuals. It's genetic and etiological similarity with West Nile virus (WNV) means that it is often detected within the same ecological niche, consequently the detection of USUV is a good indicator that the conditions are suitable for the introduction of WNV. Surveillance approaches often require detection of low viral loads within arthropod vectors. Although useful for straightforward detection, strain and genetic details can be missed which provide important information on autochthonous survival and/or reintroduction. We evaluated a pan-flavivirus screening process followed by tiled amplicon sequencing for the detection and analysis of USUV within mosquito pools. RT-PCR screening of 270 mosquito pools from a range of species revealed one positive (0.37%) in a pool of Culex modestus. Further analysis using pan-flavivirus end-point PCR produced DNA amplicons which sequencing confirmed to differ from the positive reference control. Tiled amplicon-based whole genome amplification using USUV specific primers followed by GridION sequencing produced a near full-length sequence which phylogenetic analysis placed within the African 3.2 clade. Using targeted mosquito surveillance followed by an array of molecular techniques we were able to detect and phylogenetically analyse USUV from low viral loads within infected mosquito pools. This system is useful for the initial screening and subsequent taxonomy of viruses in samples with low viral loads and high host genomic background, providing an important tool for surveillance and the analysis of circulation dynamics.
Pulmonary arterial hypertension (PAH) is characterized by progressive remodeling of the pulmonary vasculature, leading to increased pulmonary vascular resistance and chronic right ventricular (RV) pressure overload. As RV dysfunction develops, ventricular interdependence alters the structural and functional relationship between the right and left ventricles. Although normal left-sided filling pressures define PAH, growing evidence indicates that left ventricular (LV) mechanics may be substantially affected. Leftward septal displacement, pericardial constraint, and reduced pulmonary venous return contribute to chronic underfilling of the left atrium and LV, impairing ventricular geometry and contractile dynamics despite preserved intrinsic myocardial function. However, secondary myocardial remodeling in advanced disease remains debated. These alterations may lead to subclinical or overt LV dysfunction and represent an underrecognized component of PAH pathobiology. Imaging markers such as LV global longitudinal strain, LV outflow tract velocity-time integral, and left atrial strain have emerged as potential indicators of left-sided involvement and may provide additional prognostic information. In this narrative review, we summarize current evidence on the pathobiological mechanisms linking RV dysfunction to left-sided cardiac alterations and discuss the role of ventricular interdependence in the coupling of the pulmonary circulation. Understanding this interaction may help redefine PAH as a progressive biventricular syndrome and may improve risk stratification and clinical assessment.
Multiple sclerosis (MS) relapse diagnosis is impeded by 'pseudo-relapses' whilst relapse treatment lacks specificity. Before we can improve clinical care, we must first improve our understanding of relapse pathogenesis. Currently, the circulatory immune mechanisms underpinning relapse are poorly understood. We aimed to determine changes in circulatory cell counts from people with MS during relapse versus remission and their association with clinical outcomes. Data was collected retrospectively by screening 2316 patient files through which we identified 78 episodes of MS relapse and remission. From these participants full blood examination data, we calculated immune cell counts and ratios. In participants with contrast enhancing lesions on magnetic resonance imaging (MRI, n = 38), total neutrophil count (p = 0.04) and neutrophils/total white cell count (N%) was higher (p = 0.04) in relapse versus remission. Similarly, in participants with a new lesion on MRI (n = 51), total neutrophil count (p = 0.01) was significantly higher during relapse versus remission. Univariable regression analyses demonstrated that lymphocytes, the neutrophil to lymphocyte ratio, monocytes/total white cell count (M%) and N% were all associated with changes in disability scores whilst multivariable regression analyses demonstrated that M% was associated with the presence of contrast enhancing lesions. This study determined that neutrophils are elevated in the circulation of people with MS during relapse compared to remission. Additionally, neutrophils, monocytes and lymphocytes were found to be associated with clinical outcomes of relapse. These findings support the notion that alterations in circulating immune cells may play a role in MS relapse pathogenesis and may inform future biomarker studies.
Myocardial ischaemia-reperfusion injury (MIRI) exacerbates cardiomyocyte damage through oxidative stress, inflammation, and apoptosis, limiting the efficacy of reperfusion therapies. We developed PB1-Lip@M-CST, a biomimetic nanoparticle comprising procyanidin B1 (PB1)-loaded liposomes coated with macrophage cell membranes and surface-functionalized with the cardiac-specific targeting peptide CSTSMLKAC (CST). The nanoparticles were characterized for hydrodynamic size, zeta potential, core-shell morphology, retention of macrophage surface proteins (CCR2, CD11b, CD36), high encapsulation efficiency, and sustained drug release. In vitro, PB1-Lip@M-CST markedly reduced phagocytic uptake by RAW 264.7 macrophages, enhanced internalization in HL-1 cardiomyocytes in a CST-dependent manner, and provided superior protection in CoCl2-induced hypoxia-reoxygenation models by suppressing reactive oxygen species, lipid peroxidation, proinflammatory cytokines, and apoptosis. Mechanistic studies using CXCR4-overexpressing HL-1 cells and Plerixafor-treated cells confirmed that these effects were mediated via modulation of the CXCR4-associated PI3K/AKT1 signaling pathway and restoration of the BAX/BCL-2 balance. In a mouse model of MIRI, intravenous administration of PB1-Lip@M-CST prolonged systemic circulation, with markedly enhanced cardiac accumulation (highest heart AUC) and improved therapeutic index, reduced infarct size to 25.58 ± 2.96% (versus 49.22 ± 3.03% in the model group), preserved left ventricular ejection fraction at 50.42 ± 8.74%, attenuated serum injury biomarkers, and inhibited long-term fibrosis and apoptosis, with an excellent biosafety profile. These findings establish PB1-Lip@M-CST as a novel biomimetic platform that integrates macrophage membrane-mediated immune evasion with CST-directed cardiac homing to achieve cardiac-targeted delivery of PB1 and subsequent CXCR4-dependent modulation of the PI3K/AKT1 pathway in MIRI.
Hyperuricemia (HUA) is increasingly recognized as a systemic inflammatory-metabolic disorder that contributes to immune-associated renal injury. Kynurenic acid (KYNA), a tryptophan-derived metabolite with reported immunomodulatory properties, has emerged as a potential mediator linking gut metabolism and distal organ inflammation. In this study, we investigated the protective effects of astilbin (ASB) against HUA and hyperuricemia-associated renal injury using an adenine-induced goose model, which is translationally relevant because geese naturally lack functional uricase, together with monosodium urate (MSU)-challenged primary renal tubular epithelial cells. By integrating multi-omics analyses, molecular docking, and molecular biology approaches, we found that ASB reduced serum uric acid, improved renal function, and attenuated inflammatory and fibrotic changes in vivo. ASB also suppressed circulating pro-inflammatory cytokines, restored intestinal barrier-related markers, and partially corrected gut microbial dysbiosis. Untargeted metabolomics revealed that KYNA was markedly reduced under HUA conditions and was restored by ASB treatment in both intestinal contents and serum. In parallel, ASB increased IDO2 expression in intestinal and hepatic tissues. In vitro, both ASB and KYNA attenuated MSU-induced inflammatory responses, restored urate transporter expression, and suppressed TGF-β/Smad-associated profibrotic signaling in primary renal cells. Collectively, these findings support a working model in which ASB ameliorates hyperuricemia-associated sterile inflammation and renal injury partly in association with gut-linked KYNA immunometabolic remodeling, accompanied by increased IDO2 expression. Because IDO1, kynurenine, KAT activity, and receptor/pathway inhibition were not assessed, the proposed mechanism should be regarded as hypothesis-supporting rather than definitively proven.