bluuebunny/crossref_metadata_2025 huggingface dataset:
EU Values Before the Court of Justice
Authors: Spieker Luke Dimitrios
Published: July 2023

The Union’s values—enshrined in Article 2 TEU—are under pressure in several Member States. Against this backdrop, the Court of Justice has set a spectacular development in motion. With its ruling in Associação Sindical dos Juízes Portugueses it started to mobilise these values. Since then, the jurisprudence has evolved at breakneck speed. This book provides a first comprehensive study of the judicial activation of Article 2 TEU. It starts by developing the foundations of this emerging jurisprudence in empirical, doctrinal, and theoretical terms. At its heart it seeks to advance a new understanding of Article 2 TEU. The provision should be understood as featuring a dual character that resonates between two dimensions: an EU dimension limited to the EU legal order and a ‘Verbund’ dimension that extends to the common whole of the Union and its Member States. The second and third parts set out to explore the multifaceted potential of Article 2 TEU in each of these two dimensions. Finally, the book assesses the risks of placing an activated Article 2 TEU into the hands of the Luxembourg judges and proposes ways to recalibrate the jurisprudence.
Theory
Authors: Spieker Luke Dimitrios
Published: July 2023

This chapter unpacks two dimensions of Article 2 TEU that inform the further structure of this book. The provision covers two different contexts: one relating to the EU legal order and another, much broader one comprising the entirety of the EU and the Member States’ legal orders. German scholarship has theorized this latter context under the term ‘Verbund’. These dimensions of Article 2 TEU seem to correspond to different constitutional rationales. While the provision gives expression to a constitutive, thick form of constitutionalism in its EU dimension, it epitomizes a thinner, primarily restraining one in the Verbund. This leads to different functions in both spheres—as thick constitutional core of the EU legal order and as thin constitutional frame for the Verbund. Based on these insights, this chapter suggests that Article 2 TEU displays a dual character, which should guide its future judicial development.
The Court and the Legislature
Authors: Spieker Luke Dimitrios
Published: July 2023

This chapter concentrates on the relationship between the Court and the EU legislature. It demonstrates how the suggested, threefold division of primary law can encourage EU legislation. The extensive scope of primary law and the Court’s strong institutional position considerably reduce the space for legislative decision-making. Some even ascertain an over-constitutionalization of EU law. In response, they propose transferring many issues currently regulated in the Treaties to the level of secondary legislation. Based on the hierarchical division of primary law, the Court could achieve a similar outcome with less intrusive means. While retaining strict scrutiny when reviewing compliance with provisions that give specific expression to an Article 2 TEU value, the Court could leave issues regulated at the third level of Treaty provisions—and with it many important policy fields—to the legislature’s discretion. This would reduce the constraining effects of its jurisprudence and broaden the leeway for legislative decision-making.
The Court and the Treaty Makers
Authors: Spieker Luke Dimitrios
Published: July 2023

This chapter focuses on the relation between the Court and the Treaty makers. It explores whether and how Article 2 TEU could be turned into a justiciable limitation on Treaty amendments. In constitutional theory, the idea of implicit limits for constitutional amendments is based on the distinction between a primary and a secondary constituent power. The latter is empowered to amend but not to adopt a new constitution. The tipping point is reached when a constitution’s identity is affected. The chapter demonstrates how this theory could be transferred to the EU level by locating the Union’s constitutional identity in Article 2 TEU. Switching to the doctrinal level, the chapter shows further how Treaty amendments could be reviewed by the Court for their compliance with Article 2 TEU.
The Introspective Method
Authors: Spener Maja
Published: July 2023

This chapter puts forward a framework for assessing the use of introspection in scientific theorizing, based on the distinction between introspective access and introspective method. It demonstrates the value of the framework by applying it to elucidate and critically evaluate different scientific uses of introspection. Firstly, the chapter discusses past uses of introspection, focusing on central figures early German experimental psychology. Articulating their views in terms of the proposed framework brings to light the advanced and insightful state of debate among them and their recognition of the distinction between introspective access and method. Secondly, the chapter looks at the Perceptual Awareness Scale (PAS) in present-day science of consciousness. Applying the proposed framework, the chapter offers an historically informed critical appraisal of PAS. PAS’s main weakness involves proponents’ imprecision about the notion of introspection at work in it, rather than being subject to a generic worry about the use of introspection as such.
Right Here, Right Now
Authors: Debus Dorothea
Published: July 2023

Perceptual experiences provide us with a fundamental form of consciousness: In perceptual experience we are conscious of our current environment. But then, what is the nature of perceptual experience, and how could we possibly be conscious of our environment when we perceive it? Some philosophers answer these questions by offering a ‘Direct Realist’ account, others argue that we should accept a ‘Representationalist’ account of perceptual experience. Various arguments for and against both positions have been developed; but relevant arguments seem rather well-balanced, so the debate seems to have reached some sort of stand-off. The present chapter aims to offer a new vantage point from which to consider these issues afresh We reach this new vantage point by considering the observation that perceptual experiences have ‘eudaimonic’ value, that is, value with respect to a subject’s well-being. More specifically, I argue that in being in perceptual contact with a mind-independent world, the perceiving subject finds herself open to the world, and I show that and why this openness to the world contributes to the subject’s well-being. This insight seems important in its own right. But we also find that a Direct Realist can account much better for the eudaimonic value of perceptual experience than a Representationalist, which might in turn help with choosing between Representationalism and Direct Realism: As any account of perceptual experience has to account for the fact that perceptual experience has eudaimonic value, we have good reason to choose a Direct Realist account of perceptual experience over a Representationalist one.
The Dilemma for Attitude Theories of Pleasure
Authors: Pallies Daniel , Dietz Alexander
Published: July 2023

In virtue of what do we enjoy episodes of pleasure? According to the phenomenological theory of pleasure, we enjoy pleasures in virtue of having certain kinds of phenomenal experiences. According to the attitude theory of pleasure, we enjoy pleasures in virtue of having a certain kind of pro-attitude. We argue that the attitude theory faces a dilemma. Either the relevant attitude is phenomenological—in the sense that having it is necessary and sufficient for having certain phenomenal experiences—or that it is non-phenomenological. If the attitude is non-phenomenological, then the theory implies that pleasure can come radically apart from phenomenology, leading to a problem of hedonic inversion. On the other hand, if the attitude is phenomenological, then the attitude theorist must explain what sort of phenomenology is distinctive of pleasure, and in so doing they must disavow their main objection to phenomenological theories of pleasure: the so-called “heterogeneity problem.”
Inferentialism as an Alternative to Expressivism
Authors: Chrisman Matthew
Published: July 2023

Normative discourse includes statements which appear to be truth-apt expressions of normative beliefs. But normative oughts do not seem to fit cleanly amongst the natural facts. This makes many naturalistically-inclined philosophers sympathetic to some form of the expressivist view that normative statements get their meaning from how they express desire-like attitudes. However, there are serious semantic challenges for expressivism, which lead many other philosophers to accept the idea that normative statements are representational of reality after all. This chapter presents third way that derives from the general program in the theory of meaning which emphasizes the commissive role of language over any descriptive or expressive roles. Here this emphasis is used to sketch a version of metaethical inferentialism and contrast it with expressivism. The chapter concludes with some observations about new perspectives this view offers on three other issues in metaethics.
The Epistemic vs. the Practical
Authors: Kauppinen Antti
Published: July 2023

This chapter defends a Dualism of Theoretical and Practical Reason: what we epistemically ought to believe and what we practically ought to believe may come apart, and both are independently authoritative. In particular, I argue that it’s not the case that epistemic reasons bear on what we ‘just plain ought’ to believe just to the extent we have practical reason to believe epistemically correctly. Why? Because epistemic reasons give rise to authoritative demands independently of the practical pay-off of believing accordingly, as shown by the fact that it can be fitting to epistemically ‘blame’ us just because we fail to believe as we epistemically ought, even if we don’t have sufficient practical reason to believe so. The chapter also argues that we don’t need to come up with what we ‘just plain ought’ to believe, among other things because contrary responsibility responses can be simultaneously fitting in conflict cases.
The Problem of Morally Repugnant Beliefs
Authors: Smithies Declan
Published: July 2023

What is the connection between justification and truth in moral epistemology? The primary goal of this chapter is to argue that you cannot have justified false beliefs about your own moral obligations. The secondary goal is to explain why not. Some epistemologists embrace a global truth-connection in epistemology, according to which epistemic justification is always factive. In contrast, this chapter endorses a local truth-connection in moral epistemology, which says that epistemic justification is factive when it concerns your own moral obligations. To explain this, it appeals to a version of moral rationalism, which says there are necessary truths about morality that everyone has a priori justification to believe.
Robust Realism in Ethics
Authors: Ingram Stephen
Published: July 2023

Robust Realism in Ethics: Normative Arbitrariness, Interpersonal Dialogue, and Moral Objectivity defends a robustly realistic metaethical theory. It argues that, in order to capture the normative non-arbitrariness of moral choice, we must commit to the existence of robustly stance-independent, categorical, irreducibly normative, non-natural moral facts. It then shows that, by exploring the nature of interpersonal moral dialogue, robust realists can defend epistemological and meta-semantic theories that are friendly to their view. Specifically, the book defends a dualistic form of moral intuitionism on which some moral beliefs are justified on the basis of a priori intuitions, whilst others are justified on the basis of a posteriori moral experiences. And it offers a theory of ‘moral mental files’ to explain how moral terms and concepts are able to refer to robust moral facts.
Introduction
Authors: Ingram Stephen
Published: July 2023

This introductory chapter sets out the central concerns of the book, and outlines the positions and concepts that will be at issue in it. It first explains how the approach of the book—specifically, the focus on normative arbitrariness and interpersonal dialogue as a way of learning more about moral reality, moral knowledge, and moral language. It then introduces the distinction between realist theories (including naturalistic and non-naturalistic theories, and robust, relaxed and quasi-realist theories) and anti-realist theories (including error theory and two types of stance-dependence theory). The chapter ends with a brief chapter by chapter overview of the book.
Arbitrariness Charges
Authors: Ingram Stephen
Published: July 2023

Intuitions about arbitrariness and non-arbitrariness play a key role in metaethical debate. It is an interesting feature of such debate that both realists and anti-realists face ‘arbitrariness charges.’ Roughly put, to issue an arbitrariness charge against a metaethical theory is to accuse that theory of failing to capture the normative non-arbitrariness of moral choice. The precise nature of these charges remains obscure, for the concept of arbitrariness itself has never been examined in depth. This chapter clarifies the notion of arbitrariness, and then outlines five distinct arbitrariness charges—the bruteness charge, the privilege charge, the normative deficit charge, the ownership charge, and the stability charge. This sets the scene for Chapters 2–5, which ask whether realist and anti-realist theories are able to capture all the ways in which moral choices are normatively non-arbitrary.
Stance-Independence
Authors: Ingram Stephen
Published: July 2023

Having rejected the most promising stance-dependence theories in the previous two chapters, this chapter considers the prospects of a stance-independent moral ontology—that is, the ontology of moral realism. It shows that a realist view is well-placed to capture the non-arbitrariness of moral choice. It first explains how the commitment to stance-independent moral facts allows realists to avoid the arbitrariness charges that challenge stance-dependence theories. It then asks whether realists can handle the arbitrariness charges facing their own view—namely, the ownership charge and a version of the bruteness charge. It shows that answering the latter requires a commitment to categorical and (thus) irreducibly normative, non-natural reasons. This is a controversial commitment, so this chapter ends with a partial vindication of it. Specifically, it offers a ‘companions in innocence’ argument involving the normativity of non-moral needs.
Moral Reference
Authors: Ingram Stephen
Published: July 2023

The major meta-semantic question facing robust realists concerns how moral terms—like ‘right’ and ‘good’ in English—can refer to robust moral properties (given that such properties are stance-independent, non-natural, and causally inert). This chapter provides an answer to this question of semantic access. It rejects the conceptual role semantics that is often taken to be the best meta-semantic theory for robust realism, and instead defends a theory of ‘moral mental files.’ It argues that this theory is well-placed to explain certain judgements about when moral dialogue and disagreement are (and are not) possible. And it shows that the theory of moral mental files has two big payoffs for robust realism: it provides resources to accommodate certain views of moral motivation, and it affords a nuanced answer to the challenge posed by the alleged possibility of alternative normative concepts.
When not to Operate in Spinal Deformity
Authors: Passias Peter G. , Pierce Katherine E. , Dave Pooja , Lafage Renaud , Lafage Virginie , Schoenfeld Andrew J. , Line Breton , Uribe Juan , Hostin Richard , Daniels Alan , Hart Robert , Burton Douglas , Kim Han Jo , Mundis Gregory M. , Eastlack Robert , Diebo Bassel G. , Gum Jeffrey L. , Shaffrey Christopher , Schwab Frank , Ames Christopher P. , Smith Justin S. , Bess Shay , Klineberg Eric , Gupta Munish C. , Hamilton D. Kojo ,   on behalf of the International Spine Study Group
Published: July 2023

Study Design:

Retrospective review of a prospectively enrolled adult spinal deformity (ASD) database.

Objective:

To investigate what patient factors elevate the risk of sub-optimal outcomes after deformity correction.

Background:

Currently, it is unknown what factors predict a poor outcome after adult spinal deformity surgery, which may require increased preoperative consideration and counseling.

Materials and Methods:

Patients >18 yrs undergoing surgery for ASD(scoliosis≥20°, SVA≥5 cm, PT≥25°, or TK≥60°). An unsatisfactory outcome was defined by the following categories met at two years: (1) clinical: deteriorating in ODI at two years follow-up (2) complications/reoperation: having a reoperation and major complication were deemed high risk for poor outcomes postoperatively (HR). Multivariate analyses assessed predictive factors of HR patients in adult spinal deformity patients.

Results:

In all, 633 adult spinal deformity (59.9 yrs, 79% F, 27.7 kg/m2, CCI: 1.74) were included. Baseline severe Schwab modifier incidence (++): 39.2% pelvic incidence and lumbar lordosis, 28.8% sagittal vertical axis, 28.9% PT. Overall, 15.5% of patients deteriorated in ODI by two years, while 7.6% underwent reoperation and had a major complication. This categorized 11 (1.7%) as HR. HR were more comorbid in terms of arthritis (73%), heart disease (36%), and kidney disease (18%), P<0.001. Surgically, HR had greater EBL (4431ccs) and underwent more osteotomies (91%), specifically Ponte(36%) and Three Column Osteotomies(55%), which occurred more at L2(91%). HR underwent more PLIFs (45%) and had more blood transfusion units (2641ccs), all P<0.050. The multivariate regression determined a combination of a baseline Distress and Risk Assessment Method score in the 75th percentile, having arthritis and kidney disease, a baseline right lower extremity motor score ≤3, cSVA >65 mm, C2 slope >30.2°, CTPA >5.5° for an R
2 value of 0.535 (P<0.001).

Conclusions:

When addressing adult spine deformities, poor outcomes tend to occur in severely comorbid patients with major baseline psychological distress scores, poor neurologic function, and concomitant cervical malalignment.
The pine pathogen Diplodia sapinea is associated with the death of large Douglas fir trees
Authors: Ritzer Elisabeth , Schebeck Martin , Kirisits Thomas
Published: July 2023

Climate change poses severe pressures to European conifer forests. Using non‐native tree species, such as Douglas fir (Pseudotsuga menziesii), is one proposed strategy to circumvent adverse effects for forest management. However, novel forest health risks can impair the cultivation of non‐native trees. In 2022, we observed large Douglas fir trees (approximately 40–50 years old, diameter at breast height (dbh) 21–41 cm) that had recently died in spring or summer 2022 in three forest stands in Eastern Austria. Intensive resin flow, blue‐staining of the sapwood and the absence of bark‐ and wood‐boring insects indicated a fungal infection. Isolations from blue‐stained sapwood of the dead trees consistently yielded cultures of the opportunistic pathogen Diplodia sapinea. In a greenhouse wound inoculation experiment, seven D. sapinea isolates obtained from Douglas fir caused phloem necrosis, blue‐staining of sapwood and mortality and thus displayed pathogenicity towards seedlings of both Ps. menziesii and its common host, Scots pine (Pinus sylvestris). Diplodia sapinea produced significantly longer areas of blue‐stain as well as higher and faster mortality in Ps. menziesii compared to P. sylvestris. We conclude that D. sapinea substantially contributed to the death of seven of the 13 examined large Douglas fir trees. While this fungus has been described as a pathogen of young Douglas fir trees before, this is the first report that it can potentially kill large individuals of this conifer species under drought conditions. Thus, our results indicate that D. sapinea could represent a severe threat to the cultivation of Ps. menziesii in European forestry.
Evaluation of a Dementia Training Course for Staff of a Center of Dementia Care
Authors: Duarte Natália , Alves Sara , Gomes Barbara
Published: July 2023

Introduction: Literature shows poor dementia training and competencies among health and social professionals. Due to the growing prevalence of people with dementia and all the related care demands, specialized training is increasingly needed but must be effective in terms of impact on knowledge, behaviors, and attitudes. We aimed to analyze the impact of a first-level dementia training course for staff of a new specialized center for people with dementia, considering the first three levels of Kirkpatrick’s evaluation framework, namely, staff reaction (satisfaction), skills and learning (knowledge and dementia attitudes), and behavior changes. Methods: This is a single-center group pre-post design study of a 12-session online course. An online questionnaire was administered to measure satisfaction, expectations, knowledge/learning, attitudes (Dementia Attitude Scale), and new behaviors/practices. We compared perceived knowledge (Wilcoxon signed-rank test) and attitudes (paired t test). Thematic analysis explored new behaviors/practices. Results: Eighty-five professionals and 1 volunteer were included (median age 31, 92% female). Satisfaction with the training was high (median 4/5). Perceived knowledge improved (median 3–4; p < 0.001). The knowledge test median score was 70.8%. After training, participants showed better attitudes toward dementia (mean 116.5, SD 10.3, to mean 122.2, SD 11.5; p < 0.001). Most (93%) said their behavior/practice changed. Thematic analysis yielded four new behavior/practice dimensions: care provision/interaction, communication, family/caregivers, and self-confidence. Conclusions: The course improved all dimensions evaluated, suggesting it effectively provides first-level dementia training. This may be transferable to similar settings.
BIBR1532 Affects Endometrial Cell Proliferation, Migration, and Invasion in Endometriosis via Telomerase Inhibition and MAPK Signaling
Authors: Zhao Xiaoling , Luo Dan , Liu Tingting , Zhang He , Xie Yunkai , Kong Weimin
Published: July 2023

Objectives: The effect of telomerase inhibitor BIBR1532 on endometriotic cells was investigated to explore the inhibitory effect of targeting telomerase on endometriosis. Design: In vitro primary cell culture study. Participants/Materials: Primary endometrial cells derived from eutopic and ectopic endometrium in patients with endometriosis. Setting: The study was conducted in the university hospital. Methods: Paired eutopic and ectopic endometrial cells were collected from 6 patients from January 2018 to July 2021. A TRAP assay was performed to detect the telomerase activity of the cells. MTT, cell cycle, apoptosis, migration, and invasion assays were performed to study the inhibitory effect of BIBR1532. Enrichment analysis was performed to identify the key pathways involved in endometriosis progression and telomerase action. Then, Western blotting was used to investigate the expression of related proteins. Results: BIBR1532 treatment significantly inhibited the growth of eutopic and ectopic endometrial cells, with apoptosis and cell cycle signaling involved. Migration and invasion, important characteristics for the establishment of ectopic lesions, were also inhibited by BIBR1532. The MAPK signaling cascade, related to telomerase and endometriosis, was decreased in eutopic and ectopic endometrial stromal cells with the treatment of BIBR1532. Limitations: The severe side effects of telomerase inhibitors might be the main obstacle to clinical application, so it is necessary to find better drug delivery methods in vivo. Conclusions: The telomerase inhibitor BIBR1532 affects endometrial cell proliferation, migration, and invasion in endometriosis.
Deep Medullary Vein Thrombosis in Newborns: A Systematic Literature Review
Authors: Pin Jacopo Norberto , Leonardi Letizia , Nosadini Margherita , Pelizza Maria Federica , Capato Luca , Piretti Luca , Cavicchiolo Maria Elena , Simioni Paolo , Baraldi Eugenio , Perilongo Giorgio , Luciani Matteo , Sartori Stefano
Published: July 2023

Background: Deep medullary vein (DMV) thrombosis is a rare cause of brain damage in both preterm and full-term neonates. In this study, we aimed to collect data on clinical and radiological presentation, treatment, and outcome of neonatal DMV thrombosis. Methods: Systematic literature review on neonatal DMV thrombosis was carried out in PubMed, ClinicalTrial.gov, Scopus, and Web of Science up to December 2022. Results: Seventy-five published cases of DMV thrombosis were identified and analysed (preterm newborns were 46%). Neonatal distress, respiratory resuscitation, or need for inotropes were present in 34/75 (45%) of patients. Signs and symptoms at presentation included seizures (38/75, 48%), apnoea (27/75, 36%), lethargy or irritability (26/75, 35%). At magnetic resonance imaging (MRI), fan-shaped linear T2 hypointense lesions were documented in all cases. All had ischaemic injuries, most often involving the frontal (62/74, 84%) and parietal lobes (56/74, 76%). Signs of haemorrhagic infarction were present in 53/54 (98%). Antithrombotic treatment was not mentioned in any of the studies included. Although mortality was low (2/75, 2.6%), a large proportion of patients developed neurological sequelae (intellectual disability in 19/51 [37%] and epilepsy in 9/51 [18%] cases). Conclusions: DMV thrombosis is rarely identified in the literature, even if it is possibly under-recognized or under-reported. Presentation in neonatal age is with seizures and non-specific systemic signs/symptoms that often cause diagnostic delay, despite the pathognomonic MRI picture. The high rate of morbidity, which determines significant social and health costs, requires further in-depth studies aimed at earlier diagnosis and evidence-based prevention and therapeutic strategies.
A Dietary Pattern for High Estimated Total Fat Amount Is Associated with Enhanced Allergy Sensitization and Atopic Diseases among Singapore/Malaysia Young Chinese Adults
Authors: Lim Jun Jie , Reginald Kavita , Say Yee-How , Liu Mei Hui , Chew Fook Tim
Published: July 2023

Introduction: Frequent dietary patterns for fast food diets are suggested to be a risk factor for atopic disease development. Excessive dietary fats in fast foods are postulated to promote low-grade chronic inflammation. However, no studies in Asia have yet to characterize the dietary pattern for high-fat foods with atopic diseases. Thus, this study aims to assess the association between dietary fats with the prevalence of atopic diseases in an allergic cohort. Methods: Through an investigator-administered questionnaire that follows the International Study of Asthma and Allergies in Childhood (ISAAC) protocol, we evaluated the eating habits, lifestyle behaviours, sociodemographics, and atopic symptoms, and history among 11,494 young Chinese adults in Singapore and Malaysia. A skin prick test (SPT) for common house dust mites was also conducted to determine the atopic (allergic) status. We identified 1,550 atopic dermatitis (AD), 1,301 allergic asthma (AS), and 3,757 allergic rhinitis (AR) atopic cases. We derived a novel dietary index, Diet Quality based on Total Fat Amount (DQTFA), to examine the association between eating patterns for estimated total fat amount with various atopic outcomes. Results: There was a preponderance of subjects having positive SPT reaction (69.0%) with the prevalence of AR being the highest (32.7%), then AD (13.5%), and AS (11.3%). Additionally, there is a significantly higher proportion of subjects with an atopy background and atopic diseases consume diets with a high estimated mean fat amount. The adherence to a dietary pattern of the higher estimated total fat amount was shown to be strongly associated with all atopic diseases and exhibited dose-dependent responses in the univariate analysis. These associations remained significant even with the adjustments for age, gender, body mass index, use of alcohol, sedentary lifestyles, and physical activity. A dietary pattern for high-fat amount is more strongly associated with AS (adjusted odds ratio [AOR]: 1.524; 95% confidence interval [CI]: 1.216–1.725; p < 0.001) and AR (AOR: 1.294; 95% CI: 1.107–1.512; p < 0.001) compared to AD (AOR: 1.278; 95% CI: 1.049–1.559; p < 0.05). Finally, it was shown that having either one of the atopic comorbidities was strongly associated with a dietary pattern of high-fat amounts (AOR: 1.360; 95% CI: 1.161–1.594; p < 0.001). Conclusion: Our findings altogether provide initial evidence that the dietary pattern of a diet high in fat amount is associated with an increased risk of atopy and atopic diseases in young Chinese adults in Singapore and Malaysia. Balancing the consumption of dietary fats and changing personal dietary habits by choosing foods of the lower fat amount may reduce the associated odds of atopic diseases.
Usefulness of aMAP Risk Score for Predicting Recurrence after Curative Treatment for Hepatocellular Carcinoma within Milan Criteria
Authors: Ohama Hideko , Hiraoka Atsushi , Tada Fujimasa , Kato Kanako , Fukunishi Yoshiko , Yanagihara Emi , Kato Masaya , Saneto Hironobu , Izumoto Hirofumi , Ueki Hidetaro , Yoshino Takeaki , Kitahata Shogo , Kawamura Tomoe , Kuroda Taira , Suga Yoshifumi , Miyata Hideki , Hirooka Masashi , Abe Masanori , Matsuura Bunzo , Ninomiya Tomoyuki , Hiasa Yoichi
Published: July 2023

Introduction: The aMAP score is a prediction model for hepatocellular carcinoma (HCC) risk in chronic hepatitis patients. This study was conducted to elucidate the utility of this model for predicting initial recurrence of HCC in patients within the Milan criteria after undergoing curative treatment. Methods: Patients with naïve HCC within the Milan criteria (n = 1,020) and treated from January 2000 to August 2022 were enrolled. The cohort was divided into two groups according to the aMAP score (high ≥60, low <60) and then compared for recurrence-free survival (RFS) and overall survival (OS). Results: Comparisons between the high and low groups showed that etiology (HBV:HCV:HBV+HCV:NBNC = 41:79:2:37 vs. 65:589:11:196, p < 0.001), AST (36 vs. 46 IU/L, p < 0.001), and multiple HCC occurrence (15% vs. 22%, p = 0.026) were significantly different. Additionally, median RFS (59.8 vs. 30.9 months; p < 0.001) and median OS (154.1 vs. 83.4 months, p < 0.01) were greater in the low group. As for patients with HCC due to chronic viral hepatitis, there was a significant difference in median RFS between the groups (59.8 vs. 30.6 months, p < 0.001), especially for HCV-positive patients (53.1 vs. 27.2 months, p = 0.002). In patients with HCC due to a nonviral cause, the difference in median RFS between the low (70.9 months) and high (32.0 months) groups was not significant. Discussion: Findings of this retrospective study indicate a significant association of elevated aMAP with worse RFS in patients with HCC caused by chronic viral hepatitis, especially those with HCV. The aMAP score is considered useful to predict not only HCC-carcinogenesis risk but also risk of recurrence following curative treatment.
Homeopathy for Major Depressive Disorder: Protocol for N-of-1 Studies
Authors: Adler Ubiratan Cardinalli , Adler Maristela Schiabel , Cesar Amarilys de Toledo , Santos Helen de Freitas , Magalhães Patrícia Andréa da Fonseca , Nogueira Renan dos Santos , Campos Eugênio de Moura , Viana Júnior Antonio Brazil , Sanders Lia Lira Olivier
Published: July 2023

Background: N-of-1 studies allow the formal assessment of a patient’s treatment. A single participant receives different interventions the same number of times in a crossover, double-blind, randomized design. Using this methodology, we will investigate the effectiveness and safety of a standardized homeopathy protocol in treating 10 cases of major depression. Methods: The method is described below: Design: crossover double-blind placebo-controlled randomized N-of-1 studies, with at most 28 weeks of duration per participant. Participants: women and men at age over 18 years with a diagnosis of a major depressive episode given by a psychiatrist, who have presented a therapeutic response, i.e., a reduction ≥50% of the baseline depressive symptoms, self-assessed by the Beck Depression Inventory – Second Edition (BDI-II), and sustained for at least 4 weeks during an open homeopathic treatment following the protocol of the sixth edition of the Organon, with or without concomitant use of psychotropic drugs. Interventions: individualized homeopathy following the same protocol, one globule of the fifty-millesimal potency diluted in 20 mL of 30% alcohol; placebo – 20 mL of 30% alcohol, in the same posology as homeopathy. Crossover study: the participant will go through three consecutive treatment blocks, with two random and masked treatment periods (A or B), corresponding to homeopathy or placebo. Treatment periods will have 2, 4, and 8 weeks in the first, second, and third blocks, respectively. A clinically significant worsening (characterized by an augmentation in BDI-II inclusion score ≥30%) will result in the termination of study participation and resumption of the open treatment. Primary measure: progression of the depressive symptoms, self-assessed by the participant using the BDI-II scale at weeks 0, 2, 4, 8, 12, 16, 20, 24, 28 and analyzed throughout the study concerning homeopathy and placebo partitions. Secondary measures: score of the Clinical Global Impression Scale; mental and physical health scores assessed by the 12-Item Short-Form Health Survey; participant’s blind preference for treatment A or B at each block; clinical worsening; and adverse events. Data analysis: the participant, assistant physician, evaluator, and statistician will remain blinded for the study treatments until the completion of data analysis of each study. We will follow a 10-step procedure for analyzing N-of-1 observational data of each participant and conduct a meta-analysis of the combined results. Discussion: We understand that each N-de-1 study will be a chapter with its teachings in a book of ten, allowing a broader view of the effectiveness of the homeopathy protocol of the sixth edition of the Organon in treating depression.
Impact of Renal Function on the Prognosis of Patients Receiving Atezolizumab/Bevacizumab Combination Therapy and Lenvatinib Monotherapy for Unresectable Hepatocellular Carcinoma
Authors: Takada Hitomi , Yamashita Koji , Osawa Leona , Komiyama Yasuyuki , Nakakuki Natsuko , Muraoka Masaru , Suzuki Yuichiro , Sato Mitsuaki , Takano Shinichi , Fukasawa Mitsuharu , Yamaguchi Tatsuya , Maekawa Shinya , Takahashi Kazuya , Uchimura Kohei , Enomoto Nobuyuki
Published: July 2023

Introduction: Several studies have reported kidney injury caused by immune checkpoint inhibitors, and proteinuria caused by vascular endothelial growth factor inhibitors for unresectable hepatocellular carcinoma (u-HCC). We investigated the relationship between renal function and prognosis in patients with u-HCC receiving atezolizumab and bevacizumab (AB) and lenvatinib (LEN) therapy. Methods: Fifty-one patients who received AB and 50 patients who received LEN therapy were included. We analyzed prognostic factors related to the overall survival (OS), and characteristics related to renal function. Results: In patients with AB therapy, OS was shorter in patients with baseline proteinuria of 1+ or higher, as assessed by urine dipstick test, compared to those with –/± (p = 0.024). There were many cases with two or more drugs with a high risk of renal dysfunction (p = 0.019) in patients with 1+ or higher. Furthermore, OS was shorter in the group with estimated glomerular filtration rate (eGFR) grade deterioration without urinary protein-creatinine ratio (UPCR) of 2 g/g·Cre or higher than in the other groups (p = 0.027). In the group where eGFR worsened without an increase in UPCR, there were many cases with a daily salt intake of 10 g or more (p = 0.027), three or more drugs with a high risk of renal dysfunction (p = 0.021), and a history of arteriosclerosis (p = 0.021). On the other hand, in patients with LEN therapy, OS tends to be shorter in patients with proteinuria of ± or higher, compared to those without (p = 0.074). There were many cases with a daily salt intake of 10 g or more in patients with ± or higher (p = 0.002). Conclusion: In patients receiving AB and LEN therapy, baseline proteinuria was associated with OS. Renal function deterioration without proteinuria was associated with a poor prognosis in AB therapy. Excessive salt intake, preexisting atherosclerotic disease, and drug with a high risk of renal dysfunction were risk factors for renal deterioration.
A Comparison of Clinical Outcomes for Subependymal Giant Cell Astrocytomas Treated with Laser Interstitial Thermal Therapy, Open Surgical Resection, and mTOR Inhibitors
Authors: Boop Scott , Bonda David , Randle Stephanie , Leary Sarah , Vitanza Nicholas , Crotty Erin , Novotny Edward , Friedman Seth , Ellenbogen Richard G. , Durfy Sharon , Goldstein Hannah , Ojemann Jeffrey G. , Hauptman Jason S.
Published: July 2023

Introduction: Subependymal giant cell astrocytoma (SEGA) is the most common CNS tumor in patients with tuberous sclerosis complex (TSC). Although these are benign, their proximity to the foramen of Monroe frequently causes obstructive hydrocephalus, a potentially fatal complication. Open surgical resection has been the mainstay of treatment; however, this can cause significant morbidity. The development of mTOR inhibitors has changed the treatment landscape, but there are limitations to their use. Laser interstitial thermal therapy (LITT) is an emerging treatment modality that has shown promise in treatment of a variety of intracranial lesions, including SEGAs. We present a single institution, retrospective study of patients treated for SEGAs with LITT, open resection, mTOR inhibitors, or a combination of these modalities. The primary study outcome was tumor volume at most recent follow-up compared with volume at treatment initiation. The secondary outcome was clinical complications associated with treatment modality. Methods: Retrospective chart review was performed to identify patients with SEGAs treated at our institution from 2010 to 2021. Demographics, treatment information, and complications were collected from the medical record. Tumor volumes were calculated from imaging obtained at initiation of treatment and at most recent follow-up. Kruskal-Wallis nonparametric testing was used to assess differences in tumor volume and follow-up duration between groups. Results: Four patients underwent LITT (3 with LITT only), three underwent open surgical resection, and four were treated with mTOR inhibitors only. Mean percent tumor volume reduction for each group was 48.6 ± 13.8, 90.7 ± 39.8, and 67.1 ± 17.2%, respectively. No statistically significant difference was identified comparing percent tumor volume reduction between the three groups (p = 0.0513). Additionally, there was no statistically significant difference in follow-up duration between groups (p = 0.223). Only 1 patient in our series required permanent CSF diversion and 4 discontinued or decreased the dose of mTOR inhibitor due to either cost or side effects. Conclusions: Our study suggests that LITT could be considered as a treatment option for SEGAs as it was effective in reducing tumor volume with very few complications. This modality is less invasive than open resection and may be an alternative for patients who are not candidates for mTOR inhibitors. We recommend an updated paradigm for SEGA treatment which includes LITT in select cases after consideration of patient-specific factors.
Analysis of Concomitant Medications Prescribed with Antipsychotics to Patients with Dementia
Authors: Saito Yoshitaka , Oishi Satoru , Takizawa Takeya , Muraoka Hiroyuki , Yoshimura Yuki , Hashimoto Itsuki , Suzuki Ryutaro , Ono Tsuyoshi , Inada Ken
Published: July 2023

Introduction: Antipsychotics are still commonly prescribed to patients with dementia, despite the many issues that have been identified. This study aimed to quantify antipsychotic prescription in patients with dementia and the types of concomitant medications prescribed with antipsychotics. Methods: A total of 1,512 outpatients with dementia who visited our department between April 1, 2013 and March 31, 2021, were included in this study. Demographic data, dementia subtypes, and regular medication use at the time of the first outpatient visit were investigated. The association between antipsychotic prescriptions and referral sources, dementia subtypes, antidementia drug use, polypharmacy, and prescription of potentially inappropriate medications (PIMs) was evaluated. Results: The antipsychotic prescription rate for patients with dementia was 11.5%. In a comparison of dementia subtypes, the antipsychotic prescription rate was significantly higher for patients with dementia with Lewy bodies (DLB) than for those with all other dementia subtypes. In terms of concomitant medications, patients taking antidementia drugs, polypharmacy, and PIMs were more likely to receive antipsychotic prescriptions than those who were not taking these medications. Multivariate logistic regression analysis showed that referrals from psychiatric institutions, DLB, N-methyl-d-aspartate (NMDA) receptor antagonists, polypharmacy, and benzodiazepine were associated with antipsychotic prescriptions. Conclusions: Referrals from psychiatric institutions, DLB, NMDA receptor antagonist, polypharmacy, and benzodiazepine were associated with antipsychotic prescriptions for patients with dementia. To optimise prescription of antipsychotics, it is necessary to improve cooperation between local and specialised medical institutions for accurate diagnosis, evaluate the effects of concomitant medication administration, and solve the prescribing cascade.
Effects of Perfluorocarbon Use during Rhegmatogenous Retinal Detachment Surgery on Postoperative Outcomes
Authors: Sugimoto Masahiko , Kozawa Maki , Matsui Yoshitsugu , Matsubara Hisashi , Kondo Mineo , Sakamoto Taiji
Published: July 2023

Introduction: The aim of this study was to determine whether the use of perfluorocarbon liquid (PFCL) affects the rate of retinal re-attachments after an initial attachment by vitrectomy in eyes with rhegmatogenous retinal detachment (RRD). Methods: This was a retrospective, observational, multicenter study of 3,446 eyes registered in the Japanese vitreoretinal surgery treatment information database. Of these, 2,648 eyes had undergone vitrectomy as the first surgery for RRD. The re-attachment rates after the primary vitrectomy with or without PFCL were evaluated. In addition, the significance of factors affecting the re-detachments was determined by univariate and multivariate analyses. The measured outcomes were the rates of re-attachments after the primary vitrectomy with or without the use of PFCL. Results: A total of 2,362 eyes in the database were analyzed: 325 had and 2,037 did not have PFCL injected into the vitreous cavity during the vitrectomy. The rate of re-attachments was 91.5% in the PFCL group and 93.2% in the non-PFCL group (p = 0.46, χ2 test). Although there were several risk factors associated with the re-detachments in eyes without PFCL (p < 0.05, Welch’s t tests, and Fisher’s exact tests), they were not associated in eyes with PFCL use. However, multivariate analyses showed that there was no significant association between the use and the non-use of PFCL in the rate of re-detachments (β = −0.08, p = 0.46). Conclusions: The use of PFCL during the initial vitrectomy for RRD does not affect the rate of re-attachments.
Peripheral Blood-Derived CircVPS35L as a Potential Diagnostic Biomarker for Non-Small Cell Lung Cancer
Authors: Liang Nan , Zhang Xun , Zhang Luyi , Jiang Meina , Bai Huihui , Ding Chenhang , Cai Yuanting , Zhou Chengwei , Han Ying , Gong Zhaohui
Published: July 2023

Introduction: Circular RNAs (circRNAs) are dysregulated in cancers and are stably expressed in body fluids such as blood. We therefore identified and evaluated the clinical value of a newly found circRNA VPS35L (circVPS35L) as a biomarker for the diagnosis of non-small cell lung cancer (NSCLC). Methods: Reverse-transcription quantitative PCR (RT-qPCR) was used to determine the expression levels of circVPS35L in tissues, whole blood, and cell lines. The actinomycin D assay and RNase R treatment were utilized to determine the stability of circVPS35L. Receiver operating characteristic (ROC) curve analysis was conducted to predict the diagnostic value of blood-derived circVPS35L in NSCLC. Results: CircVPS35L was found to be downregulated in NSCLC tissues and cell lines. Interestingly, circVPS35L expression was significantly correlated with tumor size (p = 0.0269), histology type (p < 0.0001), and TNM stage (p = 0.0437). Importantly, circVPS35L was poorly expressed in peripheral blood of NSCLC patients when compared with healthy controls and patients with benign lung disease. ROC analysis revealed a higher diagnostic value of circVPS35L than the three conventional tumor markers (CYFR21-1, NSE, and CEA) in patients with NSCLC. Moreover, circVPS35L was highly stable in peripheral blood when exposed to undesirable conditions. Conclusion: These findings demonstrate that circVPS35L has great potential as a novel biomarker for the diagnosis of NSCLC and can be used to distinguish NSCLC from benign lung disease.
Total Lymph Node Yield Is Associated with Prolonged Survival after Neoadjuvant Chemotherapy in ypN0 Gastric Cancer Patients
Authors: Li Weikun , Shao Xinxin , Ma Fuhai , Wang Bingzhi , Xue Liyan , Hu Haitao , Kang Wenzhe , Xiong Jianping , Tian Yantao
Published: July 2023

Introduction: Lymph node status after neoadjuvant chemotherapy (NAC) plays the main role in predicting the survival of gastric cancer (GC) patients who underwent curative gastrectomy after NAC. NAC can reduce the number of involved lymph nodes. However, it is unknown whether other variables are associated with the survival outcomes for ypN0 GC patients. It is unknown whether lymph node yield (LNY) has prognostic value in ypN0 GC patients treated with NAC plus surgery. Methods: In this retrospective study, we reviewed the data of patients treated with NAC plus gastrectomy and identified those with ypN0 disease. The LNY cut-off was calculated using the X-tile program to determine the greatest actuarial survival difference. Patients were categorized into the downstaged N0 (cN+/ypN0) and natural N0 (cN0/ypN0) groups based on nodal status. Multivariate analysis was used to identify the prognostic factors and the association between LNY and prognosis. Results: A total of 211 GC patients with ypN0 status were included. The optimal LNY cut-off was 23. Kaplan-Meier analysis revealed no significant difference in overall survival between the natural and downstaged N0 groups, while ypN0 GC patients with an LNY of ≥24 had significantly longer overall survival than those with an LNY of ≤23. Univariate analysis identified that LNY, cT stage, tumor location, ypT stage, perineural invasion, lymphovascular invasion, tumor size, Mandard tumor regression grade, and extent of gastrectomy were significantly associated with overall survival. Multivariate analysis confirmed that perineural invasion (hazard ratio, 4.246; p < 0.001), lymphovascular invasion (hazard ratio, 2.694; p = 0.048), and an LNY of ≥24 (hazard ratio, 0.394; p = 0.011) were independent prognostic factors. Conclusions: Patients with natural and downstaged ypN0 GC had similar overall survival after NAC. LNY was an independent prognostic factor in these patients, and an LNY of ≥24 predicted prolonged overall survival.