bluuebunny/crossref_metadata_2025 huggingface dataset:
Realization and simulations of the new SPES Beam Cooler
Authors: Ruzzon A. , Maggiore M. , Roncolato C. , Ban G. , Cam J.F. , Gautier C. , Vandamme C.
Published: October 2023

One of the aim of the new project Selective Production of Exotic Species (SPES) is to produce and select new, neutron reach, isotopes [1,2,3,4]. The technique adopted to produce these species is the Isotope Selection On Line (ISOL) that postpones the separation of the isotopes after the beam production, using a High-Resolution Mass Spectrometer (HRMS).

In order to allow a good separation of isotopes , the transverse emittance and the energy spread of the beam should have very low values, for this reason the Beam Cooler (BC) is located between the ISOL target, i.e. the beam source, and the HRMS.

In the SPES project, where heavy isotopes are expected (mass number >100), the spectrometer resolution must be preferably higher than dm/m = 5 × 10-5 and thus the features of the beam at the entrance of the HRMS should be at least εn

95% < 8.3 × 10-3
π mm mrad and σE
< 1.5 eV.

BC devices are devoted to improve the beam features in terms of emittance and energy spread. A new BC has been designed and realized by the Laboratoire de Physique Corpuscolaire (LPC) at Caen, France, for the SPES facility at Laboratori Nazionali di Legnaro (LNL), near Padova, Italy.

BCs cool down the beam thanks to a dissipative process in which the thermal energy passes from the beam ions to another medium whose constituent is typically much lighter, Helium gas in our case. This process takes place inside a confinement system that on the one hand to limit the spread of the cooling medium, and on the other to allow the beam to continue along the required trajectory, in the presented device it is a row of radio frequency quadrupoles in an almost closed chamber.

Some specifications of the BC described in this document: the RFQ is 723 mm long, its internal radius is 5 mm; the RFQ is included in the gas chamber which is 730 mm×280 mm×220 mm. Before it there is the injection part composed by, following the beam trajectory, a grounded pipe (388 mm long) and three focusing electrodes. On the opposite side there is the extraction part with two focusing electrodes.

This document presents the main features of the new BC together with the results of a preliminary study where the beam dynamic has been simulated. The analysis embeds also the investigation of the gas distribution inside and outside the BC.

The beam dynamic simulations are based on the Simion code [5] while the estimation of the gas distribution is computed with MolFlow+ [6].

Simulations show that accurately setting the BC leads to a large improvement of the emittance while the energy spread still needs to be improved. Limiting the gas pressure in the acceleration zone seems to allow the required final boost.
A Bayesian tune of the Herwig Monte Carlo event generator
Authors: La Cagnina Salvatore , Kröninger Kevin , Kluth Stefan , Verbytskyi Andrii
Published: October 2023

The optimisation (tuning) of the free parameters of Monte
Carlo event generators by comparing their predictions with data is
important since the simulations are used to calculate experimental
efficiency and acceptance corrections, or provide predictions for
signatures of hypothetical new processes in experiments. We present
a tuning procedure that is based on Bayesian reasoning and that
allows for a proper statistical interpretation of the results. The
parameter space is fully explored using Markov Chain Monte Carlo. We
apply the tuning procedure to the Herwig7 event generator with both
the cluster and the string hadronization models and a large set of
measurements from hadronic Z-boson decays produced at LEP in
 e
+
e
- collisions. Furthermore, we introduce a coherent
propagation of uncertainties from the realm of parameters to the
realm of observables and we show the effects of including
experimental correlations of the measurements. To allow comparison
with the approaches of other groups, we repeat the tuning
considering weights for individual measurements.
Macroplastic deposition and flushing in the Meuse river following the July 2021 European floods
Authors: Hauk Rahel , van Emmerik Tim H M , van der Ploeg Martine , de Winter Winnie , Boonstra Marijke , Löhr Ansje J , Teuling Adriaan J
Published: October 2023

Rivers play an important role in the macroplastics transport and retention dynamics in the environment. Therefore, gaining an understanding of these processes is vital in order to help determine the fate of macroplastic in the environment. During flood events the transport of floating macroplastic is known to increase. We compared plastic accumulation and flushing on sixteen riverbanks along the Dutch Meuse river during the period that includes the July 2021 extreme flood to plastic accumulation on the same riverbanks as during normal discharge conditions between 2018 and 2021. Here we show that following the flood small macroplastic categories (

<
2.5

cm) were flushed from the riverbanks, while larger soft plastic fragments (2.5–50 cm) and wet tissues were deposited. We found that for all plastic categories and for all riverbanks averaged, the plastic accumulation rate during the July 2021 flood was higher than that which would be expected for that time of year. However, the average accumulation rate for all locations during the period that included the flood was lower than the average accumulation rate over the Dutch winter (Oct/Nov–Feb/Mar). Our results show that litter category composition following the July 2021 flood differed from normal conditions. This indicates that plastic deposition and remobilization processes on riverbanks differ between extreme flood and annually average conditions. These observations contribute to a better understanding of the fate of macroplastic in the environment in terms of the drivers of both its transport and deposition.
Quantum reading of quantum information
Authors: Khabbazi Oskouei Samad , Mancini Stefano , Rexiti Milajiguli
Published: October 2023

We extend the notion of quantum reading to the case where the information to be retrieved, which is encoded into a set of quantum channels, is of quantum nature. We use two-qubit unitaries describing the system-environment interaction, with the initial environment state determining the system’s input-output channel and hence the encoded information. The performance of the most relevant two-qubit unitaries is determined with two different approaches: (i) one-shot quantum capacity of the channel arising between environment and system’s output; (ii) estimation of parameters characterizing the initial quantum state of the environment. The obtained results are mostly in (qualitative) agreement, with some distinguishing features that include the CNOT unitary.
Integration on minimal
Z22
-superspace and emergence of space
Authors: Aizawa N , Ito Ren
Published: October 2023

We investigate the possibilities of integration on the minimal

Z

2
2

-superspace. Two definitions are taken from the works by Poncin and Schouten and we examine their generalizations. It is shown that these definitions impose some restrictions on the integrable functions. We then introduce a new definition of integral, which is inspired by our previous work, and show that the definition does not impose restrictions on the integrable functions. An interesting feature of this definition is the emergence of a spatial coordinate which means that the integral is defined on

R

2

despite the fact that the

(
0
,
0
)

part of the minimal

Z

2
2

-superspace is

R

.
Malaria
Authors: Wayne Marta L. , Bolker Benjamin M.
Published: October 2023

Malaria, possibly the most important infectious disease on the planet, is transmitted to humans through various species of Anopheles mosquitoes. Malaria tends to be endemic and rarely reaches out of the tropics, being limited by the ecological niche of its mosquito vectors. The most widespread strains of malaria are typically chronic and debilitating, rather than causing acute infection and death, but the cumulative impact of malaria on humanity is enormous. ‘Malaria’ considers the complexity of the disease; the history of human malaria; and the strategies employed against the disease, including the historical use of quinine to treat malaria and the insecticide DDT to control mosquito populations. More recent strategies include drugs such as chloroquine and artemisinin, household insecticide spraying and insecticide-treated bed nets, and vaccines to reduce childhood mortality. While single methods are ineffective for controlling or eradicating malaria, governments and agencies can deploy different combinations of tools that are appropriate to the local situation.
SARS-CoV-2/COVID-19
Authors: Wayne Marta L. , Bolker Benjamin M.
Published: October 2023

SARS-CoV-2 is the virus that caused the recent COVID-19 pandemic. Its global impact comes from its transmissibility, its ability to be transmitted by asymptomatic people, and its intermediate virulence. Comparing the related SARS-CoV-1 and MERS viruses, which have caused severe disease without generating a pandemic, shows differences in both virulence (infection and case fatality rates) and transmissibility. The chapter considers whether SARS-CoV-2 spilled over into human populations through transmission between bats and humans or a leak from a virology lab. It describes how SARS-CoV-2 continues to evolve in the human population, considering the transmission and virulence of the variants that emerged over the course of the pandemic. While lockdowns, distancing, and masking were the only control methods early in the pandemic, rapidly developed vaccines offer the possibility of keeping up with continued transmission and evolution of SARS-CoV-2 into the future.
Looking ahead
Authors: Wayne Marta L. , Bolker Benjamin M.
Published: October 2023

This chapter shows how our understanding of how diseases are transmitted, and the development of vaccines and treatments that can close the compatibility filter, has revolutionized disease management. But what is the outlook for the future control of infectious diseases? A future free of infectious diseases is simply unrealistic. Living things have parasitized one another since the beginning of life itself, and will certainly continue to do so. New diseases will be created by mutation or recombination of existing ones, and existing diseases will continually evolve to escape our methods of control. Urbanization and population growth will change the ways in which we contact animal hosts, leading to new zoonoses. Controlling disease depends on combining strategies to prevent transmission and protect individuals, as well as communicating the importance of these efforts to the public. We can minimize the impact of diseases even if we can never fully eliminate them.
The existential question
Authors: Loughlin Martin
Published: October 2023

The unwritten and evolutionary character of the British constitution relies on tacit understandings that shape the values of its governing institutions. But a growing loss of faith by the political class in customary ways of governing is leading to a loss of trust in the authority of its inherited governing institutions. This has led successive governments to advance various reforms but, despite these, Britain is nowhere near to adopting a modern written constitution. In this sense, it might be asked whether there is any longer a British constitution.
Reconfiguring the state
Authors: Loughlin Martin
Published: October 2023

This chapter examines how changes in the scope of British authority have affected constitutional principle. Nominally, all components of the empire were subordinate to illimitable parliamentary sovereignty, but in reality many informal constraints existed. The EU posed a further challenge to parliamentary sovereignty, since EU law superseded British law and its hyper-rationalist structure ran contrary to British constitutional practice. Since Brexit cannot restore the status quo ante, withdrawal complicates present arrangements, especially in relation to the UK’s devolution settlement. What relevance, the chapter asks, do modern concepts like state, citizen, and nation have to our understanding of the constitution today?
Civil liberty
Authors: Loughlin Martin
Published: October 2023

This chapter looks at how rights and liberties have been guaranteed by the constitution. Blackstone divided liberty into three categories: personal security, personal liberty, and private property, to be upheld by Parliament, jury trial, and habeas corpus. Dicey believed in the rule of law, upheld by an implicit partnership between Parliament and the judiciary. With the modern extension of powers, the government’s administrative powers have come increasingly under the supervision of the courts, bringing legality closer to the core of the constitution. The growing influence of European human rights law has resulted in judges acting as guardians of enumerated rights, but recent government proposals seek to circumscribe that role.
The Occupation
Authors: Andrew Dudley
Published: October 2023

This chapter focuses on French cinema during the Occupation by the Germans. Central offices (the COIC) monitored the streamlined exhibition and distribution of films. As the scam productions rife during the 1930s disappeared, average revenues grew, even though a third fewer films were made. Despite censorship, viewers stuck with French cinema, since there was little foreign competition. Escapist comedies, historical romances, and biopics dominated, but critics primarily focused on self-enclosed dark dramas, such as Robert Bresson’s Les Anges du péché, H.-G. Clouzot’s Le Corbeau, and Marcel Carné’s Les Visiteurs du soir. The latter’s Les Enfants du paradis, the grandest film of the era, opened just as the Germans capitulated and it was celebrated as representing France’s return to international acclaim in cinema.
Cahiers du Cinéma rewrites French cinema
Authors: Andrew Dudley
Published: October 2023

This chapter considers how Cahiers du Cinéma rewrote French cinema. François Truffaut’s Un Certain tendence du cinéma français provoked outrage after he diagnosed French cinema as suffering aesthetic anaemia and needing a transfusion. Truffaut alleged that the directors and screenwriters ruling French cinema betrayed the art form because they betrayed the literary “Tradition of Quality” from which they presumptuously claimed to have descended. The chapter explores wavering distinctions between the authentic and the specious whereby adaptation need not always lead to mediocrity since it can help forge cinematic style—as in the case of Journal d’un curé de campagne. Because they took on serious subjects and novels, René Clément and Clouzot became embattled filmmakers in a cinematic cold war of the 1950s between the industry and the Cahiers du Cinéma critics. Among the auteurs the young critics supported were Jacques Becker and Jean-Pierre Melville. Their styles were in tune with the American cultural influence of the decade and a youthful verve which mainline directors had trouble imitating even when they used the fresh faces of Brigitte Bardot and Jeanne Moreau.
Looking at and beyond “le cinéma du look”
Authors: Andrew Dudley
Published: October 2023

This chapter expounds on the dominance of the cinéma du look after the popularity of Jean-Jacques Beineix’s Diva. Serge Daney campaigned against this splashy advertising (poster) style since it veers away from the cinema of discovery and depth that he, like Bazin, espoused. As French cinema tried to regain its lost prestige, it foregrounded visual style and continues to do so in its excellent animation sector. The chapter also considers alternatives to this florid mannerist style in stripped down, abstemious even, masochistic films. Thérèse (1986) and later Tous les matins du monde (1991) each reached the hearts of over a million French citizens, then played well outside the nation, despite being toned down, meditative biopics.
α-Tocotrienol in rice bran enhances steroidogenesis in mouse Leydig cell via increased gene expression of steroidogenic acute regulatory protein and induction of its mitochondrial translocation
Authors: Terada Naofumi , Nagase Tomoaki , Kayooka Hiromi , Adachi Yusuke , Kato Eisuke
Published: October 2023

Rice is a staple food in the Asian region and one of the world's major energy sources. Testosterone is a steroid hormone that maintains physical, sexual, and cognitive ability, and its decline causes health problems like late-onset hypogonadism. Evaluation of various grain extracts showed rice bran to stimulate testosterone secretion from Leydig model cells. α-Tocotrienol was found as a bioactive compound in rice bran, and mechanistic analysis showed the stimulation of steroid hormone synthesis through enhanced gene expression of steroidogenic acute regulatory protein as well as inducing mitochondrial localization of the protein. Preliminary study showed an increasing trend in serum testosterone levels in mice by oral intake of α-tocotrienol. These results suggest that α-tocotrienol intake may be effective in preventing symptoms caused by low testosterone levels.
Acrogeria, an exceptional cause of acro-osteolysis
Authors: Valayer Simon , Hickman Geoffroy , Petit Antoine , Solal Martine Cohen , De Sandre Giovannoli Annachiara , Bourrat Emmanuelle
Published: October 2023

This case report presents a previously unreported mutation in the LMNA gene associated with acrogeria, highlighting a distinct entity within the spectrum of laminopathies. Considering acrogeria as a potential diagnosis should be taken into account for patients with early-onset acro-osteolysis.
RBPMS regulates cardiomyocyte contraction and cardiac function through RNA alternative splicing
Authors: Gan Peiheng , Wang Zhaoning , Bezprozvannaya Svetlana , McAnally John R , Tan Wei , Li Hui , Bassel-Duby Rhonda , Liu Ning , Olson Eric N
Published: October 2023

Aims

RNA binding proteins play essential roles in mediating RNA splicing and are key post-transcriptional regulators in the heart. Our recent study demonstrated that RBPMS (RNA binding protein with multiple splicing) is crucial for cardiac development through modulating mRNA splicing, but little is known about its functions in the adult heart. In this study, we aim to characterize the post-natal cardiac function of Rbpms and its mechanism of action.

Methods and results

We generated a cardiac-specific knockout mouse line and found that cardiac-specific loss of Rbpms caused severe cardiomyocyte contractile defects, leading to dilated cardiomyopathy and early lethality in adult mice. We showed by proximity-dependent biotin identification assay and mass spectrometry that RBPMS associates with spliceosome factors and other RNA binding proteins, such as RBM20, that are important in cardiac function. We performed paired-end RNA sequencing and RT–PCR and found that RBPMS regulates mRNA alternative splicing of genes associated with sarcomere structure and function, such as Ttn, Pdlim5, and Nexn, generating new protein isoforms. Using a minigene splicing reporter assay, we determined that RBPMS regulates target gene splicing through recognizing tandem intronic CAC motifs. We also showed that RBPMS knockdown in human induced pluripotent stem cell-derived cardiomyocytes impaired cardiomyocyte contraction.

Conclusion

This study identifies RBPMS as an important regulator of cardiomyocyte contraction and cardiac function by modulating sarcomeric gene alternative splicing.
What about chronotropic incompetence in heart failure with mildly reduced ejection fraction? Clinical and prognostic implications from the Metabolic Exercise combined with Cardiac and Kidney Indexes score dataset
Authors: Magrì Damiano , Gallo Giovanna , Piepoli Massimo , Salvioni Elisabetta , Mapelli Massimo , Vignati Carlo , Fiori Emiliano , Muthukkattil Melwyn Luis , Corrà Ugo , Metra Marco , Paolillo Stefania , Maruotti Antonello , Di Loro Pierfrancesco Alaimo , Senni Michele , Lagioia Rocco , Scrutinio Domenico , Emdin Michele , Passino Claudio , Parati Gianfranco , Sinagra Gianfranco , Correale Michele , Badagliacca Roberto , Sciomer Susanna , Di Lenarda Andrea , Agostoni Piergiuseppe , Filardi Pasquale Perrone
Published: October 2023

Aims

Chronotropic incompetence (CI) is a strong predictor of outcome in heart failure with reduced ejection fraction, however no data on its clinical and prognostic impacts in heart failure with mildly reduced ejection fraction (HFmrEF) are available. Therefore, the study aims to investigate, in a large multicentre HFmrEF cohort, the prevalence of CI as well as its relationship with exercise capacity and its prognostic role over the cardiopulmonary exercise testing (CPET) parameters.

Methods and results

Within the Metabolic Exercise combined with Cardiac and Kidney Indexes (MECKI) database, we analysed data of 864 HFmrEF out of 1164 stable outpatients who performed a maximal CPET at the cycle ergometer and who had no significant rhythm disorders or comorbidities. The primary study endpoint was cardiovascular (CV) death. All-cause death was also explored. Chronotropic incompetence prevalence differed depending on the method (peak heart rate, pHR% vs. pHR reserve, pHRR%) and the cut-off adopted (pHR% from ≤75% to ≤60% and pHRR% ≤ 65% to ≤50%), ranging from 11% to 62%. A total of 84 (9.7%) CV deaths were collected, with 39 (4.5%) occurring within 5 years. At multivariate analysis, both pHR% [hazard ratio 0.97 (0.95–0.99), P < 0.05] and pHRR% [hazard ratio 0.977 (0.961–0.993), P < 0.01] were associated with the primary endpoint. A pHR% ≤ 75% and a pHRR% ≤ 50% represented the most accurate cut-off values in predicting the outcome.

Conclusion

The study suggests an association between blunted exercise-HR response, functional capacity, and CV death risk among patients with HFmrEF. Whether the CI presence might be adopted in daily HFmrEF management needs to be addressed in larger prospective studies.
Sexual selection buffers the negative consequences of population fragmentation on adaptive plastic responses to increasing temperatures
Authors: Iglesias-Carrasco Maider , Taboada Beatriz , Lozano Miguel , Carazo Pau , Garcia-Roa Roberto , Rodriguez-Exposito Eduardo , Garcia-Gonzalez Francisco
Published: October 2023

Whether sexual selection facilitates or hampers the ability to plastically respond to novel environments might depend on population structure, via its effects on sexual interactions and associated fitness payoffs. Using experimentally evolved lines of the seed beetle Callosobruchus maculatus, we tested whether individuals evolving under different sexual selection (monogamy vs. polygamy) and population spatial structure (metapopulation vs. undivided populations) treatments differed in their response across developmental thermal conditions (control, hot, or stressful) in a range of fitness and fitness-associated traits. We found that individuals from subdivided populations had lower lifetime reproductive success at hot temperatures, but only in lines evolving under relaxed sexual selection, revealing a complex interaction between sexual selection, population structure, and thermal environmental stress on fitness. We also found an effect of population structure on several traits, including fertility and adult emergence success, under exposure to high thermal conditions. Finally, we found a strong negative effect of hot and stressful temperatures on fitness and associated traits. Our results show that population structure can exacerbate the impact of a warming climate, potentially leading to declines in population viability, but that sexual selection can buffer the negative influence of population subdivision on adaptation to warm temperatures.
Estimation of time-variable friction parameters using machine learning
Authors: Ishiyama Ryo , Fukuyama Eiichi , Enescu Bogdan
Published: October 2023

The laboratory-derived rate- and state-dependent friction (RSF) law governs rock friction. Although a number of studies have investigated the RSF friction parameters, they are not fully understood yet within a physical framework. In this study, we estimated the variation of RSF parameters during stick-slip cycles, in order to have insights into the temporal variation of fault conditions during slipping, which may help understand the relation between the change in friction parameters and the generation of gouge particles. To get a more refined understanding of the evolution of RSF parameters, we estimated these parameters for each of the hundreds of stick-slip events that occurred on laboratory faults during an experiment. We used experiment data for which the gouge particles were removed from the laboratory faults at the beginning of each experiment; this procedure made possible to evaluate the influence of the gouge layer evolution on the variation of the RSF parameters. Since the amount of data was very large, we adopted a random forest (RF) machine learning approach for data analysis. The RF model was trained on simulated friction data and then applied to the experiment stick-slip event data to estimate the RSF parameters. To generate simulated friction data of stick-slip events, a one-degree-of-freedom spring-slider model governed by the RSF law was assumed. From plots of friction change as a function of displacement, some representative features were extracted to account for the RSF parameters and were used as input to the RF algorithm. Using the RF approach, we captured the variation of the RSF parameters a, $b - a$ and ${D}_{\mathrm{c}}\ $defined in the RSF law. The results show that during a first transient phase, the parameter a becomes smaller, while parameters $b - a$ and ${D}_{\mathrm{c}}$ become larger, as the gouge layer becomes thicker. The variation of the RSF parameters becomes less pronounced during the following steady-state phase. These results suggest that the variation of RSF friction parameters may be related to the evolution of the gouge layer.
Molecular Point-of-Care Testing for Hepatitis C: Available Technologies, Pipeline, and Promising Future Directions
Authors: Ivanova Reipold Elena , Shilton Sonjelle , Donolato Marco , Fernandez Suarez Marta
Published: October 2023

Hepatitis C virus (HCV) remains a major public health problem, despite the availability of effective treatments. In many areas, the ability to diagnose HCV infection at the point of care is key to scaling up access to care and treatment. To achieve this, an accurate, easy-to-use, and affordable diagnostic tool is required—this would enable decentralized testing and the creation of one-stop centers to eliminate gaps in the care cascade, which would help reach the millions of people with undiagnosed HCV infection in low- and middle-income countries and high-risk populations in high-income countries. In this review, we examine the current state of point-of-care molecular technologies, the advantages and limitations of currently available devices (both near- and true-point-of-care), the potential of molecular testing to transform diagnostic medicine in the future, and the challenges that need to be addressed for broader adoption of this technology in routine clinical practice.
Low birth weight and reduced postnatal nutrition lead to cardiac dysfunction in piglets
Authors: McPeek Ashley C , Patton Breanna , Columbus Daniel A , Olver T Dylan , Rodrigues Lucas A , Sands Jade M , Weber Lynn P , Ferguson David P
Published: October 2023

Heart disease is the leading cause of death in humans and evidence suggests early life growth-restriction increases heart disease risk in adulthood. Therefore, this study sought to investigate the effects of low birth weight (LBW) and postnatal restricted nutrition (RN) on cardiac function in neonatal pigs. We hypothesized that LBW and RN would reduce cardiac function in pigs but this effect would be reversed with refeeding. To investigate this hypothesis, pigs born weighing <1.5 kg were assigned LBW, and pigs born >1.5 kg were assigned normal birth weight (NBW). Half the LBW and NBW pigs underwent ~25% total nutrient restriction via intermittent suckling (assigned RN) for the first 4 wk post-farrowing. The other half of piglets were allowed unrestricted suckling access to the sow (assigned NN). At 28 d of age (weaning), pigs were weaned and provided ad libitum access to a standard diet. Echocardiographic, vascular ultrasound, and blood pressure (BP) measurements were performed on day 28 and again on day 56 to assess cardiovascular structure and function. A full factorial three-way ANOVA (NN vs. RN, LBW vs. NBW, male vs. female) was performed. Key findings include reduced diastolic BP (P = 0.0401) and passive ventricular filling (P = 0.0062) in RN pigs at 28 d but this was reversed after refeeding. LBW piglets have reduced cardiac output index (P = 0.0037) and diastolic and systolic wall thickness (P = 0.0293 and P = 0.0472) at 56 d. Therefore, cardiac dysfunction from RN is recovered with adequate refeeding while LBW programs irreversible cardiac dysfunction despite proper refeeding in neonatal pigs.
Applied physiology of the liver
Authors: Stieger Bruno , Mertens Joachim C.
Published: October 2023

The liver is situated between the gut and the systemic circulation and therefore all substances entering the body via the gut must pass through this organ. The liver produces bile which drains into the upper small intestine and this fluid can therefore be used for excretory functions operating in reverse to the blood flow from the gut. The position of the liver within the circulation is reflected by five key physiological functions of the liver: it is important in the control of body energy homoeostasis, it is central to amino acid homoeostasis and to biotransformation, it synthesizes the majority of plasma proteins, and it forms bile. The aim of this chapter is to summarize these key liver functions and put them for selected processes into a pathophysiological perspective.
Liver function tests and assessment of liver function
Authors: Mousa Omar Y. , Kamath Patrick S.
Published: October 2023

Liver inspection was used in ancient times to predict health and the future. In the twentieth century, the value of serum transaminases and bilirubin was determined in the diagnosis of liver disease. Assessment of global hepatic function can be achieved using biochemical testing of the liver alone or in combination with complications of portal hypertension. However, measurement of liver enzyme levels does not reflect liver function, therefore it is recommended to use the term liver biochemical tests rather than liver function tests. These tests include serum bilirubin, transaminases, alkaline phosphatase, gamma-glutamyl transferase, and 5′-nucleotidase. They have many clinical applications and are essential non-invasive tools to evaluate liver diseases, determine severity and progression, and measure treatment outcomes. Albumin and prothrombin time are important tests of hepatic synthetic function. Dynamic tests of liver performance are non-invasive tools that are described in the literature but are rarely used in clinical practice.
Bacterial and parasitic infections of the liver
Authors: Kedarisetty Chandan Kumar , Jain Mayank , Selvan Thamarai S. , Bhargav Varanasi Y. , Venkataraman Jayanthi
Published: October 2023

The liver with its unique dual blood supply is susceptible to bacterial and parasitic infections. Fungal infections are usually rare but more often encountered in immunocompromised individuals. Clinical presentation in an individual varies from being asymptomatic to abnormal liver biochemistry (granulomatous liver disorders) to symptomatic hepatitis manifesting with fever, jaundice, or as discomfort/pain being localized to the upper abdomen by space-occupying lesions as in liver abscesses. Diagnosis at times is challenging, but a reasonable knowledge on the regional prevalence of various parasitic infections, a detailed history, and a good physical examination complemented by molecular diagnostic and liver imaging can help one to make an early diagnosis with initiation of appropriate treatment. This chapter considers various aspects of pathogenicity, epidemiology, clinical presentation, diagnosis, and management of major bacterial and parasitic infections of the liver and biliary tree.
Benign liver tumours
Authors: Shankar Sadhana , Florou Evangelia , Srinivasan Parthi
Published: October 2023

Benign liver tumours are commonly identified and usually asymptomatic, however, upon discovery, may pose a challenge in characterization and management. Cavernous haemangioma is the most common benign liver tumour. It may present in various sizes and numbers and if significantly large can cause clinical symptoms due to thrombosis, rupture, and haemorrhage. Among the benign tumours of hepatocellular origin, hepatocellular adenoma and focal nodular hyperplasia are frequently seen in young females, with the former having variants which carry the potential for malignant transformation. Biliary hamartomas and focal fatty lesions are often encountered intraoperatively and may be misconstrued as malignant deposits. Due to their byzantine clinical behaviour, a thorough knowledge of the vast array of benign liver tumours and their aetiopathogenesis is sine qua non for management.
Medical management of portal hypertension and its complications
Authors: Khan Mohammad Qasim , Kamath Patrick S.
Published: October 2023

The major complications of advanced liver disease—namely, variceal haemorrhage, ascites, and hepatic encephalopathy—are consequences of portal hypertension. Portal hypertension is a pathological increase in the portal venous pressure defined by an increase in the hepatic sinusoidal pressure to 6 mmHg or greater, most commonly measured by indirect assessment utilizing the gradient between the portal vein and the inferior vena cava, defined as the hepatic venous pressure gradient. Although the diagnosis and management of portal hypertension has advanced over the past decades, substantial morbidity and mortality remain. The natural history, pathophysiology, aetiology, and management of portal hypertension and its complications, including variceal haemorrhage, ascites, and hepatic encephalopathy, are discussed in this chapter.
Budd–Chiari syndrome, veno-occlusive disease, and secondary vascular diseases of the liver
Authors: Sánchez-Velázquez Patricia , Burdío Fernando
Published: October 2023

As most of the vascular disorders of the liver are rare and not often encountered by clinicians, the best evidence available has been collected through cohort studies rather than randomized clinical trials. These disorders, although they rarely affect more than 5/10,000 people, are usually focused on the young population and the lack of appropriate disease-specific management could lead to significant morbidity and mortality. The disorders can be differentiated into two groups: those which affect liver inflow, such as non-cirrhotic portal vein thrombosis, the most frequent; and those which involve the liver outflow as the main cause of posthepatic portal hypertension, that is, the Budd–Chiari syndrome and veno-occlusive syndrome. This chapter describes the main features and treatment options of these disorders.
Treatment of hepatocellular carcinoma
Authors: Mazzaferro Vincenzo , Droz dit Busset Michele , Virdis Matteo
Published: October 2023

Surgical options (liver resection and transplantation) represent the mainstay of treatment for hepatocellular carcinoma (HCC). By providing the only chance of cure they identify prognostic categories and complement a number of locoregional and systemic therapies. Considering the outcome of surgical interventions, HCC ‘operability’ exerts a predominantly prognostic role with the consequence that resectability can be considered at any stage of intrahepatic HCC presentation, either upfront or after non-surgical treatments have reduced or controlled the tumour. In this chapter, the role of guidelines is analysed by comparing different approaches. Although current guidelines only capture part of the potentials of surgical therapies for HCC, common trends will be reviewed. Several technical and strategic innovations have emerged in recent years, such as the laparoscopic/robotic minimally invasive techniques, the predictability and management of postoperative liver failure in patients with chronic liver diseases, and the safe expansion of liver resection to borderline indications. Tumour response to non-surgical therapies is a very effective driver for indicating surgical intervention, with particular reference to liver transplantation in patients with HCC beyond conventional indications. As treatments of primary liver cancer continue to grow with development of new drugs and devices, surgical interventions maintain a central role in any therapeutic algorithm, particularly when curative rather than palliative perspectives are pursued. Although a comprehensive description of modern management of HCC is beyond the scope of this chapter, a focus on the surgical conditions influencing the treatment results in HCC patients is proposed.
Primary neoplasms of the liver
Authors: Lerut Jan , Lai Quirino
Published: October 2023

Non-hepatocellular, non-cholangiocellular cancers are rare tumours which cover a broad spectrum. Their diagnostic and therapeutic algorithm is not standardized due to their rare occurrence, protean clinical manifestations, and evolution. This chapter gives an overview about the hepatic vascular tumours and about different types of sarcomatous tumours based on the analysis of the recent literature and the findings of the detailed European Liver Transplant Registry–European Liver Intestine Transplantation Association vascular tumour-study. Special attention is given to the role of liver transplantation (LT). In the case of vascular tumours, surgical resection offers the best results. Unfortunately, partial resection is only possible in a minority (<10%) of patients due to the multifocal nature of the lesions. HEHE, even when limited extrahepatic disease is present, is an excellent indication for LT; conversely, LT is an absolute contraindication in HHS due to the universal and early, deadly recurrence. The outlook of patients harbouring undifferentiated embryonal liver sarcoma and biliary embryonal rhabdomyosarcoma has been markedly improved by combining aggressive (neo-)adjuvant chemotherapy and surgery; radiotherapy does not seem to further improve outcome. LT is without doubt of value in case R0 surgery cannot be reached. Conversely, there is no place for LT in the treatment of carcinosarcoma and leiomyosarcoma. In order to improve the outlook of all these rare liver neoplasms, multimodal treatments combining radical surgery, multidrug and/or target chemotherapies, and eventually external beam radiotherapy are urgently needed. LT will occupy a more and more important place in this field of modern hepatobiliary oncology.
Liver transplantation
Authors: McKenna Greg J.
Published: October 2023

Liver transplantation is now a widely accepted therapy for liver failure and complications from liver disease. The liver is complex with a multitude of synthetic, metabolic, excretory, and immunoregulatory functions. Understanding these and the pathophysiology of liver injury allows for better managing liver failure and recognizing the role for liver transplantation. When a patient with advanced liver disease is referred to a transplant centre, a multidisciplinary evaluation is undertaken which examines six things: indications, contraindications, cancer screening, anatomical evaluation, psychiatric assessment, and prioritization. Organ allocation systems such as the Model for End-Stage Liver Disease with sodium (MELD-Na) score are used to assess mortality risk and determine priority for transplant. After a liver transplant, there is a high potential for complications, and the key to improving outcomes and reducing mortality is to avoid these complications if possible, and effectively managing any that may occur. Additionally, it is imperative to manage immunosuppression to appropriately suppress the alloimmune response against donor alloantigen to prevent rejection, and also minimize side effects and avoid the drug toxicities that also impact survival. There has been great progress over the last five decades and both short- and long-term survival are excellent, with an approximately 92% survival at 1 year and 60% survival at 10 years.
Live donor liver transplantation
Authors: Finotti Michele , Testa Giuliano
Published: October 2023

Liver transplantation is the treatment of choice for end-stage liver diseases and hepatocellular carcinoma. Living donor liver transplantation, in an era of organ shortage and a large number of candidates, can be an additional source of grafts and, in selected cases, can be considered to be the technique of choice. Donor selection, with a step-by-step approach, is crucial for the safety of the donor and the good outcome of the recipient. Left or right donor hepatectomy, performed in an open, laparoscopic, or robotic fashion, is demanding. Some important technical aspects have to be considered before and during the surgical procedure, especially in the biliary tract dissection and graft venous outflow. Complex reconstructions for the venous outflow, the portal vein, the hepatic artery, and the hepatic duct may be necessary. In this context, additional tools to help the surgeon planning the surgical strategy are under evaluation.
Post-cholecystectomy biliary injury
Authors: Mohkam Kayvan , Mabrut Jean-Yves , Rode Agnès , Lesurtel Mickaël
Published: October 2023

Iatrogenic biliary injury is the most severe complication of cholecystectomy associated with costly management, impaired quality of life, and increased mortality compared to the general population. Its main risk factors are anatomical, nature of the pathology (acute cholecystitis), and surgeon dependent. There are several classifications which provide an anatomical description of the injury, guide therapy, and allow comparison of outcomes between series. An optimal workup should precede any treatment of post-cholecystectomy biliary injury to fully understand the extent of the biliary damage and identify potential associated vascular injury. Therapeutic management is complex and requires early referral to a tertiary expert centre with a multidisciplinary approach involving hepatobiliary surgeons, interventional radiologists, and endoscopists. More importantly a continuous effort should be sustained to encourage a culture of safety in laparoscopic cholecystectomy to decrease the risk of biliary injury.
Biliary atresia
Authors: Ramachandran Priya
Published: October 2023

Neonatal cholestasis syndrome includes a wide spectrum of diseases with varying clinical phenotypes all of which present with cholestasis in infancy. Biliary atresia is one of the causes of cholestasis and mandates early diagnosis and corrective surgery. Biliary atresia is also the commonest cause for liver transplantation in children. The disease predominantly affects the extrahepatic biliary tree. A sequential treatment strategy of a Kasai portoenterostomy followed by liver transplantation in unsuccessful cases has resulted in a survival rate of about 90% in these children. It is important to differentiate biliary atresia from the other diseases in the neonatal cholestasis spectrum. The diagnostic algorithms have evolved to include more non-invasive procedures with high diagnostic accuracy. The outcome of the Kasai operation depends on several factors and optimizing the outcome results in jaundice clearance in approximately half of the children. Understanding the multifactorial aetiology of biliary atresia and the consequent pathogenic pathways involved will enable the development of novel therapeutic measures which will help reduce the disease burden.
Cystic diseases of the biliary system
Authors: Heinrich Stefan
Published: October 2023

Cystic diseases of the biliary system are generally rare with choledochal cysts being most frequent. The differentiation of uncomplicated cysts from cystic or even premalignant or malignant diseases may be challenging. Therefore, knowledge of the clinical and radiological appearances of these abnormalities is crucial for clinical judgement. Intraductal papillary neoplasms of the bile duct carry a comparatively high risk for malignancy and reveal biological characteristics comparable to the main duct type of intraductal papillary mucinous neoplasms of the pancreas. Depending on the assumed disease, conservative management is possible or oncological surgery mandatory.
Primary sclerosing cholangitis
Authors: Neuberger James
Published: October 2023

Primary sclerosing cholangitis (PSC) is a rare disease affecting both adults and children. In adults, PSC may present asymptomatically, with symptoms or signs of cholestasis or with liver failure. In children, PSC usually presents with a syndrome resembling autoimmune hepatitis. Diagnosis depends primarily on demonstrating strictures and dilatations of the biliary tree; liver histology is rarely indicated to make the diagnosis. Treatment is symptomatic: ursodeoxycholic acid is not recommended for newly diagnosed patients; those with PSC/autoimmune hepatitis overlap syndrome should be offered immunosuppressive therapy. Biliary dilatation may be helpful for those with a dominant extrahepatic biliary stricture. PSC is closely linked to inflammatory bowel disease (mainly ulcerative colitis). The most common causes of death are liver failure and cholangiocarcinoma. Cholangiocarcinoma is often diagnosed during the first year after presentation but may occur at any time. In those with PSC and colitis, there is a significantly increased risk of colon cancer so annual colonoscopy is recommended. Liver transplantation is effective treatment for those with end-stage liver disease or intractable symptoms, but survival is reduced compared with other indications because of recurrent disease.
Arterial thrombosis: pathophysiological background
Authors: Badimon Lina , Vilahur Gemma
Published: October 2023

The formation of a complex blood clot within a coronary artery triggers the thrombotic events. Arterial thrombosis comprises four basic pathways: platelet activation and aggregation, blood coagulation with fibrin formation, inflammation, and fibrinolysis. These pathways interact with each other and with the vessel wall, in the special regulatory conditions set by the local blood flow to trigger the formation of a thrombus with a determined growth rate, mass, and stability on top of an atherosclerotic plaque. In this chapter, cellular and molecular mechanisms of thrombus formation, from platelet aggregation to coagulation, fibrinolysis, and inflammation, are described. Determinants of thrombus growth, comprising both local factors, as well as severity and type of exposed atherosclerotic tissue, and systemic thrombogenic risk factors and comorbidities, are also conveyed as important drivers in the final thrombotic episode. The thrombus mass and stability at the time of coronary plaque disruption/destabilization influences the severity of clinical symptoms.
Platelet P2Y12 inhibitors
Authors: Pareek Manan , Bhatt Deepak L.
Published: October 2023

Adenosine diphosphate P2Y12 receptor antagonists inhibit platelet activation and subsequent aggregation. These agents may be used either alone or as part of dual antiplatelet therapy regimens with aspirin. P2Y12 inhibitors have proven useful in the treatment and prevention of several atherosclerotic cardiovascular conditions, including coronary, cerebrovascular, and peripheral artery disease. While clopidogrel served as the principal P2Y12 inhibitor for a decade, the more potent agents, prasugrel and ticagrelor, are now preferred in many settings, particularly in patients with an acute coronary syndrome. This chapter summarizes the main pharmacological properties of contemporary oral and intravenous P2Y12 inhibitors, and the major randomized controlled trials related to their clinical indications.