Hepatic manifestations of hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia is a genetic condition of abnormal blood vessel formation resulting from an imbalance of pro- and anti-angiogenic products of the transforming growth factor ß/bone morphogenetic protein signalling pathway which contributes to vascular remodelling and maintenance. Hepatic vascular malformations are common although less frequently symptomatic, but may result in high-output cardiac failure, portal hypertension and biliary ischaemia. Whilst the understanding of the genetic and cell signalling pathways that are the hallmark of hereditary haemorrhagic telangiectasia have been clarified, there remain challenges in therapy for these patients. Only patients with symptomatic hepatic vascular malformations require treatment, with most (63%) responding to first-line medical therapy. For non-responders, bevacizumab is effective in reducing cardiac output in those with heart failure secondary to hepatic vascular malformations as well as other manifestations of the disease. Although liver transplantation is the only curative option, optimal timing is critical. Novel anti-angiogenetic drugs and those that target aberrant cell signalling pathway are being explored.

Tracking the invasive and euryhaline pikeperch Sander lucioperca in the lower River Thames using acoustic telemetry indicates no movements into areas of relatively high salinity.

Native to Central and Eastern Europe, the euryhaline pikeperch Sander lucioperca can acclimatize to elevated salinity levels (e.g., up to 30‰), but it remains unknown whether their invasive populations use this ability to inhabit and/or disperse through brackish waters, such as estuaries and inshore areas. To test whether invasive pikeperch show a propensity to move into areas of relatively high salinity, their spatial use and movement patterns (e.g., home range, distances moved, and movement rates) were assessed using acoustic telemetry in the upper River Thames estuary, southeast England. Analyses revealed that individual pikeperch were capable of moving relatively long distances in a short time (e.g., speeds up to 70 m min-1), with movement patterns associated more with tidal state and elevation at the water surface (both assumed to relate to changes in salinity) than diurnal changes. There were no recorded movements of any pikeperch into the more saline, downstream waters of the estuary where salinity levels were recorded to over 40‰, with the mean salinity in the most downstream area where pikeperch were detected being 1.39‰ (range of logger: 1.22-1.71). The results suggest that these pikeperch did not use high salinity waters when less saline waters were available, and thus the risk that they will use to move through high salinity areas to expand their invasive range appears low. Accordingly, efforts to minimize risks of the further dispersal of invasive pikeperch populations can focus on control and containment programmes within fresh waters.

A multi-population approach supports common patterns in marine growth and maturation decision in Atlantic salmon (Salmo salar L.) from southern Europe.

This study provides a regional picture of long-term changes in Atlantic salmon growth at the southern edge of their distribution, using a multi-population approach spanning 49 years and five populations. We provide empirical evidence of salmon life history being influenced by a combination of common signals in the marine environment and population-specific signals. We identified an abrupt decline in growth from 1976 and a more recent decline after 2005. As these declines have also been recorded in northern European populations, our study significantly expands a pattern of declining marine growth to include southern European populations, thereby revealing a large-scale synchrony in marine growth patterns for almost five decades. Growth increments during their sea sojourn were characterized by distinct temporal dynamics. At a coarse temporal resolution, growth during the first winter at sea seemed to gradually improve over the study period. However, the analysis of finer seasonal growth patterns revealed ecological bottlenecks of salmon life histories at sea in time and space. Our study reinforces existing evidence of an impact of early marine growth on maturation decision, with small-sized individuals at the end of the first summer at sea being more likely to delay maturation. However, each population was characterized by a specific probabilistic maturation reaction norm, and a local component of growth at sea in which some populations have better growth in some years might further amplify differences in maturation rate. Differences between populations were smaller than those between sexes, suggesting that the sex-specific growth threshold for maturation is a well-conserved evolutionary phenomenon in salmon. Finally, our results illustrate that although most of the gain in length occurs during the first summer at sea, the temporal variability in body length at return is buffered against the decrease in post-smolt growth conditions. The intricate combination of growth over successive seasons, and its interplay with the maturation decision, could be regulating body length by maintaining diversity in early growth trajectories, life histories, and the composition of salmon populations.

Nonmalignant portal vein thrombi in patients with cirrhosis consist of intimal fibrosis with or without a fibrin-rich thrombus.

BACKGROUND AND AIM: Portal vein thrombosis (PVT) is a common complication of cirrhosis. The exact pathophysiology remains largely unknown, and treatment with anticoagulants does not lead to recanalization of the portal vein in all patients. A better insight into the structure and composition of portal vein thrombi may assist in developing strategies for the prevention and treatment of PVT. APPROACH AND RESULTS: Sixteen prospectively and 63 retrospectively collected nonmalignant portal vein thrombi from patients with cirrhosis who underwent liver transplantation were included. Histology, immunohistochemistry, and scanning electron microscopy were used to assess structure and composition of the thrombi. Most recent CT scans were reanalyzed for thrombus characteristics. Clinical characteristics were related to histological and radiological findings. All samples showed a thickened, fibrotic tunica intima. Fibrin-rich thrombi were present on top of the fibrotic intima in 9/16 prospective cases and in 21/63 retrospective cases. A minority of the fibrotic areas stained focally positive for fibrin/fibrinogen (16% of cases), von Willebrand factor (VWF; 10%), and CD61 (platelets, 21%), while most of the fibrin-rich areas stained positive for those markers (fibrin/fibrinogen, 100%; VWF, 77%; CD61, 100%). No associations were found between clinical characteristics including estimated thrombus age and use of anticoagulants and presence of fibrin-rich thrombi. CONCLUSION: We demonstrate that PVT in patients with cirrhosis consists of intimal fibrosis with an additional fibrin-rich thrombus in only one-third of cases. We hypothesize that our observations may explain why not all portal vein thrombi in patients with cirrhosis recanalize by anticoagulant therapy.

High summer macrophyte cover increases abundance, growth, and feeding of juvenile Atlantic salmon.

Aquatic habitats are severely threatened by human activities. For anadromous species, managing freshwater habitats to maximize production of more, larger juveniles could improve resilience to threats in marine habitats and enhance population viability. In some juvenile salmonid habitats, complexity created by large substrates provides resources and reduces competitive interactions, thereby promoting juvenile production. In lowland rivers, which lack large substrates, aquatic plants might provide similar complexity and enhance fish productivity. To test the influence of aquatic plants on juvenile Atlantic salmon and sympatric brown trout in a lowland river, we directly manipulated the cover of the dominant macrophyte, Ranunculus, in nine sites during summer and autumn for two years. We quantified the abundance, site retention and growth of salmon and trout under high, medium or low Ranunculus cover. To investigate the effects of Ranunculus cover on feeding opportunities and interspecific competition, we quantified available prey biomass and body size, fish diet composition and compared dietary niche overlap. Experimentally increased Ranunculus cover supported higher salmon abundance in summer and autumn, and higher site retention and growth of salmon in summer. Trout abundance and growth were not influenced by Ranunculus cover, but trout site retention doubled in high, relative to low, cover sites. Despite the weak effects of Ranunculus cover on prey availability, salmon and trout inhabiting high cover sites consumed larger prey and a higher biomass of prey. Furthermore, dietary niche overlap was lower in high, relative to low, cover sites, suggesting that abundant Ranunculus reduced interspecific competition. This field experiment shows that high Ranunculus cover can support more and better growing juvenile salmon, and facilitate foraging and co-existence of sympatric salmonid species. Maintaining or enhancing natural macrophyte cover can be achieved through sympathetic in-river and riparian vegetation management and mitigating pressures on them, such as sediment inputs and low flows, or through planting. Further research should test whether macrophyte cover benefits propagate to subsequent life stages, particularly juvenile overwintering associated with high mortality. This knowledge, in combination with our findings, would further clarify whether beneficial juvenile habitat can improve the viability of at-risk salmonid populations. Overall, our findings suggest that the aims of river restoration might be achieved through promotion of in-stream aquatic vegetation.

Dose summation and image registration strategies for radiobiologically and anatomically corrected dose accumulation in pelvic re-irradiation.

BACKGROUND: Re-irradiation (reRT) is a promising technique for patients with localized recurrence in a previously irradiated area but presents major challenges. These include how to deal with anatomical change between two courses of radiotherapy and integration of radiobiology when summating original and re-irradiation doses. The Support Tool for Re-Irradiation Decisions guided by Radiobiology (STRIDeR) project aims to develop a software tool for use in a commercial treatment planning system to facilitate more informed reRT by accounting for anatomical changes and incorporating radiobiology. We evaluated three approaches to dose summation, incorporating anatomical change and radiobiology to differing extents. METHODS: In a cohort of 21 patients who previously received pelvic re-irradiation the following dose summation strategies were compared: (1) Rigid registration (RIR) and physical dose summation, to reflect the current clinical approach, (2) RIR and radiobiological dose summation in equivalent dose in 2 Gy fractions (EQD2), and (3) Patient-specific deformable image registration (DIR) with EQD2 dose summation. RESULTS: RIR and physical dose summation (Strategy 1) resulted in high cumulative organ at risk (OAR) doses being 'missed' in 14% of cases, which were highlighted by EQD2 dose summation (Strategy 2). DIR (with EQD2 dose summation; Strategy 3) resulted in improved OAR overlap and distance to agreement metrics compared to RIR (with EQD2 dose summation; Strategy 2) and was consistently preferred in terms of clinical utility. DIR was considered to have a clinically important impact on dose summation in 38% of cases. CONCLUSION: Re-irradiation cases require individualized assessment when considering dose summation with the previous treatment plan. Fractionation correction is necessary to meaningfully assess cumulative doses and reduce the risk of unintentional OAR overdose. DIR can add clinically relevant information in selected cases, especially for significant anatomical change. Robust solutions for cumulative dose assessment offer the potential for future improved understanding of cumulative OAR tolerances.

Density-dependence and environmental variability have stage-specific influences on European grayling growth.

Fish somatic growth is indeterminate and can be influenced by a range of abiotic and biotic variables. With climate change forecast to increase the frequency of warming and unusual discharge events, it is thus important to understand how these variables currently influence somatic growth and how that might differ for specific age-classes and/ or life stages. Here, we used a 17-year dataset from a chalk stream in southern England to identify the abiotic and biotic influences on the growth of juvenile, sub-adult and adult life stages of European grayling (Thymallus thymallus), a cold-water riverine salmonid. The results revealed that interannual variations in grayling growth were well described by annual- and site-specific abiotic and biotic explanatory variables. We found divergent responses between life stages to increased temperature and unusual discharge during the main growth period with, for example, elevated temperatures related to increased juvenile growth but reduced sub-adult growth, and high discharge events related to increased sub-adult growth yet reduced juvenile growth. Conversely, stage-specific grayling abundance negatively influenced growth at each life stage, though only juvenile growth was impacted by the abundance of a competitor species, brown trout (Salmo trutta). These results emphasise the merits of testing a wide range of environmental and biological explanatory variables on fish growth, and across life stages. They also reveal the importance of maintaining high habitat heterogeneity in rivers to ensure all life stages can reduce their competitive interactions and have access to adequate flow and thermal refugia during periods of elevated environmental stress.

Predicting how environmental conditions and smolt body length when entering the marine environment impact individual Atlantic salmon Salmo salar adult return rates.

Populations of Atlantic salmon Salmo salar have experienced precipitous declines in abundance since the 1970s. This decline has been associated with reduced numbers of adult salmon returning to fresh water from their marine migration, i.e., their marine return rates (MRR). Thus, understanding the factors that affect MRR is of crucial conservation importance. The authors used a state-space model with a 13-year time series of individually tagged salmon mark-recapture histories on the River Frome, southern England, to test the effect of smolt body length on their MRR. In addition to smolt length, the model tested for the influence of environmental covariates that were representative of the conditions experienced by the smolts in the early stages of their seaward migration, i.e., from the lower river to the estuary exit. The model indicated that, even when accounting for environmental covariates, smolt body length was an important predictor of MRR. Although larger smolts have a higher probability of returning to their natal river as adults than smaller smolts, and one-sea-winter salmon have a survival rate twice as high as multi-sea-winter salmon, the actual biological mechanisms underpinning this phenomenon remain uncertain. These results have important applications for salmon conservation, as efforts to bolster salmon populations in the freshwater environment should consider methods to improve smolt quality (i.e., body size) as well as smolt quantity.

Co-targeting of CXCR4 and hedgehog pathways disrupts tumor-stromal crosstalk and improves chemotherapeutic efficacy in pancreatic cancer.

Pancreatic cancer (PC) remains a therapeutic challenge because of its intrinsic and extrinsic chemoresistance mechanisms. Here, we report that C-X-C motif chemokine receptor 4 (CXCR4) and hedgehog pathways cooperate in PC chemoresistance via bidirectional tumor-stromal crosstalk. We show that when PC cells are co-cultured with pancreatic stellate cells (PSCs) they are significantly more resistant to gemcitabine toxicity than those grown in monoculture. We also demonstrate that this co-culture-induced chemoresistance is abrogated by inhibition of the CXCR4 and hedgehog pathways. Similarly, the co-culture-induced altered expression of genes in PC cells associated with gemcitabine metabolism, antioxidant defense, and cancer stemness is also reversed upon CXCR4 and hedgehog inhibition. We have confirmed the functional impact of these genetic alterations by measuring gemcitabine metabolites, reactive oxygen species production, and sphere formation in vehicle- or gemcitabine-treated monocultures and co-cultured PC cells. Treatment of orthotopic pancreatic tumor-bearing mice with gemcitabine alone or in combination with a CXCR4 antagonist (AMD3100) or hedgehog inhibitor (GDC-0449) displays reduced tumor growth. Notably, we show that the triple combination treatment is the most effective, resulting in nearly complete suppression of tumor growth. Immunohistochemical analysis of Ki67 and cleaved caspase-3 confirm these findings from in vivo imaging and tumor measurements. Our findings provide preclinical and mechanistic evidence that a combination of gemcitabine treatment with targeted inhibition of both the CXCR4 and hedgehog pathways improves outcomes in a PC mouse model.

Abnormal preoperative cognitive screening in aged surgical patients: a retrospective cohort analysis.

BACKGROUND: Preoperative cognitive dysfunction has been associated with adverse postoperative outcomes. There are limited data characterising the epidemiology of preoperative cognitive dysfunction in older surgical patients. METHODS: This retrospective cohort included all patients ≥65 yr old seen at the Washington University preoperative clinic between January 2013 and June 2018. Cognitive screening was performed using the Short-Blessed Test (SBT) and Eight-Item Interview to Differentiate Aging and Dementia (AD8) screen. The primary outcome of abnormal cognitive screening was defined as SBT score ≥5 or AD8 score ≥2. Multivariable logistic regression was used to identify associated factors. RESULTS: Overall, 21 666 patients ≥65 yr old completed screening during the study period; 23.5% (n=5099) of cognitive screens were abnormal. Abnormal cognitive screening was associated with increasing age, decreasing BMI, male sex, non-Caucasian race, decreased functional independence, and decreased metabolic functional capacity. Patients with a history of stroke or transient ischaemic attack, chronic obstructive pulmonary disease, diabetes mellitus, hepatic cirrhosis, and heavy alcohol use were also more likely to have an abnormal cognitive screen. Predictive modelling showed no combination of patient factors was able to reliably identify patients who had a <10% probability of abnormal cognitive screening. CONCLUSIONS: Routine preoperative cognitive screening of unselected aged surgical patients often revealed deficits consistent with cognitive impairment or dementia. Such deficits were associated with increased age, decreased function, decreased BMI, and several common medical comorbidities. Further research is necessary to characterise the clinical implications of preoperative cognitive dysfunction and identify interventions that may reduce related postoperative complications.

Sinus of Valsalva Aneurysms: A Review with Perioperative Considerations.

The sinuses of Valsalva are outpouchings in the aortic root just distal to the aortic valve that serve several physiologic functions. Aneurysm of this segment of the aorta is quite rare and infrequently encountered in clinical practice. Due to the rarity of sinus of Valsalva aneurysms, there is a lack of controlled trials and most of the literature consists of case reports and series. Here, the authors review the currently available literature to discuss the anatomy and normal function of the aortic root, as well as disease pathology and diagnostic imaging considerations. Using reported cases, the authors also will discuss considerations for cardiac anesthesiologists in the perioperative period.

Warm winters and cool springs negatively influence recruitment of Atlantic salmon (Salmo salar L.) in a southern England chalk stream.

Previous work suggests that juvenile salmon recruitment in rain-fed rivers is negatively influenced by warm and wet winters and cool springs. We tested whether this is generally applicable to a southern England chalk stream characterized by comparatively stable discharges and temperatures. We found that warm spawning and cool emergence temperatures negatively influenced juvenile recruitment between 2015 and 2020. Together these findings suggest an ability to predict juvenile productivity from water temperature records around spawning and fry emergence, thereby allowing time for management interventions in years of unfavourable temperatures.

Anesthetic Considerations for Transcatheter Tricuspid Valve Repair.

The development of transcatheter approaches for heart valve repair and replacement procedures have revolutionized the field of structural cardiology and cardiac anesthesiology. With the recently reported benefits of transcatheter mitral repair procedures, there has been increasing focus on transcatheter tricuspid repair technologies. Currently, there are multiple transcatheter tricuspid repair devices that are undergoing feasibility testing, and each device has its own unique procedural considerations. This review discusses the anesthetic management of transcatheter tricuspid repair by describing the causes of tricuspid regurgitation, the currently available transcatheter tricuspid repair devices, the procedural considerations relevant to the cardiac anesthesiologist, and pearls for proper intraprocedural image guidance via transesophageal echocardiography.

Acute Presentation of Bioprosthetic Mitral Valve Thrombosis in a Patient on Venoarterial Extracorporeal Membranous Oxygenation.

The management of patients presenting with bioprosthetic valve thrombosis presents a major clinical challenge from a diagnostic and management standpoint. This patient population becomes especially challenging to manage when presenting with cardiogenic shock and additional risks for bleeding. In this clinical conference, the authors present the case of a 64-year-old male who developed intraoperative bioprosthetic mitral valve thrombosis and cardiogenic shock necessitating support with venoarterial extracorporeal membrane oxygenation. The discussion focuses on the diagnostic challenges with transesophageal echocardiography and the difficulty in determining the proper approach to systemic anticoagulation.

Anesthetic Considerations for Aortic Arch Stenting.

With advances in modern day imaging techniques for the aorta, there has been an increasing incidence of vascular diseases involving the aortic arch. Historically, the only treatment option for arch disease has been open arch replacement under circulatory arrest conditions with or without selective cerebral perfusion. However, this open procedure has significant morbidity and mortality, especially in elderly patients with multiple comorbidities. To potentially mitigate the risks associated with open replacement, endovascular arch repair has gained momentum as an alternative treatment option. Currently, aortic arch stenting is being trialed in multiple international medical centers across Europe and the United States. The outcomes data available thus far are promising, which suggest that there likely will be an increase in patients being referred for aortic arch stenting procedures in the future. In this emerging technology review, multiple aspects of the aortic arch stenting procedure are discussed including the currently available endovascular arch devices, the unique surgical and anesthetic considerations for arch stent implantation, and the early outcomes data published to date.

Anesthetic Considerations for the Transcatheter Management of Mitral Valve Disease.

The development of transcatheter interventions to provide a minimally invasive alternative to open surgical repair has revolutionized the care of patients with valvular heart disease. Recently, this technology has been expanded to allow for the treatment of pathology of the mitral valve. This review discusses the anesthetic considerations for patients presenting for transcatheter management of mitral valve disease, including transcatheter mitral valve replacement (TMVR) and transcatheter mitral valve repair (TMVRep). The initial focus is on the current literature on transcatheter interventions for mitral valve pathologies as well as current and developing technology for TMVR and TMVRep. The authors' institutional experience with anesthetic management for the TMVR and TMVRep procedures is described, including potential pitfalls and complications, concluding with a discussion of the role of transesophageal echocardiography in the care of this patient population.

Co-Operation between Aneuploidy and Metabolic Changes in Driving Tumorigenesis.

Alterations from the normal set of chromosomes are extremely common as cells progress toward tumourigenesis. Similarly, we expect to see disruption of normal cellular metabolism, particularly in the use of glucose. In this review, we discuss the connections between these two processes: how chromosomal aberrations lead to metabolic disruption, and vice versa. Both processes typically result in the production of elevated levels of reactive oxygen species, so we particularly focus on their role in mediating oncogenic changes.

Review: Allee effects in social species.

Allee effects have important implications for many aspects of basic and applied ecology. The benefits of aggregation of conspecific individuals are central to Allee effects, which have led to the widely held assumption that social species are more prone to Allee effects. Robust evidence for this assumption, however, remains rare. Furthermore, previous research on Allee effects has failed to adequately address the consequences of the different levels of organisation within social species' populations. Here, we review available evidence of Allee effects and model the role of demographic and behavioural factors that may combine to dampen or strengthen Allee effects in social species. We use examples across various species with contrasting social structure, including carnivores, bats, primates and eusocial insects. Building on this, we provide a conceptual framework that allows for the integration of different Allee effects in social species. Social species are characterised by nested levels of organisation. The benefits of cooperation, measured by mean individual fitness, can be observed at both the population and group levels, giving rise to "population level" and "group level" Allee effects respectively. We also speculate on the possibility of a third level, reporting per capita benefits for different individuals within a group (e.g. castes in social insects). We show that group size heterogeneity and intergroup interactions affect the strength of population-level demographic Allee effects. Populations with higher group size heterogeneity and in which individual social groups cooperate demonstrate the weakest Allee effects and may thus provide an explanation for why extinctions due to Allee effects are rare in social species. More adequately accounting for Allee effects in social species will improve our understanding of the ecological and evolutionary implications of cooperation in social species.

The Perioperative Management of Ascending Aortic Dissection.

Acute aortic syndromes are a distinct group of pathologies involving the wall of the aorta that present acutely and can be potentially fatal unless treated in a timely fashion. The syndrome is dominated by aortic dissections, which comprise ≥95% of all such presentations. Those involving the ascending aorta are particularly lethal and require specific and early surgical treatment compared to dissections involving other parts of the aorta. The surgical repair of an ascending aortic dissection presents multiple challenges to the anesthesiologist. Thoughtful management throughout the perioperative period is critical for minimizing the significant morbidity and mortality associated with this condition. In this narrative review, we provide an overview of the perioperative management of patients presenting for the surgical repair of an ascending aortic dissection. Preoperative discussion focuses on assessment, hemodynamic management, and risk stratification. The intraoperative section includes an overview of anesthetic management, transesophageal echocardiographic assessment, and coagulopathy, as well as surgical considerations that may influence anesthetic management.

Anesthetic Considerations for Transcatheter Pulmonary Valve Replacement.

The introduction of transcatheter therapy for valvular heart disease has revolutionized the care of patients with valvular disorders. Pathologic regurgitation or stenosis of the pulmonary valve, right ventricular outflow tract, or a right ventricle-to-pulmonary artery conduit represent emerging indications for transcatheter therapy. To date, minimal literature exists detailing the anesthetic management of patients undergoing transcatheter pulmonary valve replacement. In this review, the pathophysiology and indications for transcatheter pulmonary valve replacement and possible complications unique to this procedure are reviewed. Anesthetic management, including preoperative assessment, intraoperative considerations, and early postoperative monitoring, are discussed.