bluuebunny/crossref_metadata_2025 huggingface dataset:
‘The Extreme Non-Zionist, Apolitical Concept of Jewish Public Life’
Authors: Giladi Rotem
Published: August 2021

Chapter 3—the second to explore the theme Voice—considers Shabtai Rosenne’s response to Hersch Lauterpacht’s reproach of Israel’s aversion to the individual right of petition. Rosenne castigated Lauterpacht for expressing an ‘extreme non-Zionist, apolitical concept of Jewish public life and the Jewish place on the international scene’ challenging, thereby, Lauterpacht’s representative capacity and ideological credentials. The right of petition and human rights writ large were, for Rosenne, assimilationist projects. Both were premised on individual, not collective, Jewish subjecthood; both were antithetical to how Zionism constructed the legal-political status of Jews and saw the Diaspora as the root cause of the modern Jewish predicament. Moreover, by investing individual Jews with the capacity to appear before international bodies, the right of petition challenged Israel’s sovereign claim to paramount Jewish voice in the world arena; Lauterpacht’s reproach thus challenged the sovereign capacity of Rosenne and Robinson to speak for Jewish interests with authority.
‘A False and Perverse Doctrine’
Authors: Giladi Rotem
Published: August 2021

Chapter 5 explores the origins of Jacob Robinson and Shabtai Rosenne’s ambivalence towards the Genocide Convention and Raphael Lemkin. At its core was their reading of the Convention as the extension of interwar protection of minority rights—in essence, as a programme of Diaspora Nationalism. The Convention was predicated on a competing model of Jewish nationalism that, following Simon Dubnow, identified the Diaspora—not Palestine—as the proper locus for Jewish national revival. It challenged Zionism’s core assumptions about the Jewish condition and the solution it prescribed to the ‘Jewish Question’. A return to minority rights, after the Holocaust, undermined Zionism’s achievement of majority status in Palestine and negated the need for a Jewish state to guarantee the protection of Jews. Both Robinson and Rosenne had previously subscribed to Dubnow’s teachings; the chapter traces their ideological transformations: from investment in to disenchantment with national autonomy, minority rights, and Dubnow’s theories.
Health Outcomes and Health Inequalities
Authors: Schneider Simone M. , Roots Ave , Rathmann Katharina
Published: August 2021

This chapter explains concepts and empirical variation regarding health outcomes, access to healthcare, and health inequalities. Access to healthcare is highlighted as a potential mediator or transition point linking characteristics of the broader policy context to health outcomes and their distribution across population groups. The chapter also discusses potential indicators and measurement issues considered relevant for cross-national comparative research and introduces the data sources and methodology for the figures that follow in the regional outlook and country chapters. It provides a short empirical overview of cross-national variation in health outcomes, health inequalities, and access to healthcare in Europe.
Sweden
Authors: Blomqvist Paula , Winblad Ulrika
Published: August 2021

This chapter provides an extended look at health politics and the tax-financed, universal health system in Sweden. It traces the historical development of the Swedish healthcare system, characterized by a shifting relationship between a powerful, interventionist state and self-governing county-level governing institutions. Starting in the late 1980s, despite broad political agreement about the need to adapt the system and make it more patient-centered, there has been debate over most health reforms, particularly over the role of markets and private actors, with legislative votes largely following the left–right political party divide. Nevertheless, reforms like the introduction of private actors, mostly publicly financed and regulated, the enhancement of patient choice, measures to reduce waiting times, and other changes in the formerly nearly all-public system have taken place without seriously undermining the health system’s fundamentally solidaristic character.
Human-Compatible Artificial Intelligence
Authors: Russell Stuart
Published: August 2021

Following the analysis given by Alan Turing in 1951, one must expect that AI capabilities will eventually exceed those of humans across a wide range of real-world-decision making scenarios. Should this be a cause for concern, as Turing, Hawking, and others have suggested? And, if so, what can we do about it? While some in the mainstream AI community dismiss the issue, I will argue that the problem is real: we have to work out how to design AI systems that are far more powerful than ourselves while ensuring that they never have power over us. I believe the technical aspects of this problem are solvable. Whereas the standard model of AI proposes to build machines that optimize known, exogenously specified objectives, a preferable approach would be to build machines that are of provable benefit to humans. I introduce assistance games as a formal class of problems whose solution, under certain assumptions, has the desired property.
Introduction
Authors: Evangelista Stefano
Published: August 2021

Drawing on definitions by Walter Pater and Charles Baudelaire, the introduction sees literary cosmopolitanism as a characteristic phenomenon of the turn of the century. It argues that writers looked back to important formulations of world citizenship in Kant’s Enlightenment philosophy, while also understanding cosmopolitanism as part of the material conditions of their own modernity. The introduction provides an historical overview of the complex relationship between cosmopolitanism and nationalism, from the seminal theories of Johann Gottfried Herder to the end of the nineteenth century. It charts how cosmopolitanism became attached to a distinctive, often gendered social identity connoted by worldliness and privilege, which often masked anxieties about migration and international mobility. It argues that literature played a key role in determining the cultural, linguistic, ethical, and affective possibilities for cosmopolitanism in the fin de siècle, and that our own approach to the literature of this period should become more international and comparative.
Practical Thought
Authors: Dancy Jonathan
Published: August 2021

This is a collection of papers published between 1977 and 2017. The papers focus on moral metaphysics, on holism in the theory of reasons and ethical particularism, on the theory of motivation, and on the development of ethical intuitionism. In moral metaphysics the distinction between resultance and supervenience is taken to have significant consequences. In moral theory the general line is that there are plenty of moral reasons but no moral principles. In the theory of motivation a case is made for the idea that the reasons for which we act are matters of fact, real or supposed. In the history of intuitionism, I try to show the benefits of taking H. A. Prichard seriously.
On Moral Properties
Authors: Dancy Jonathan
Published: August 2021

This paper is about the relation of resultance, signalled by the ‘because’ in ‘that was wrong because it was dishonest’. It distinguishes resultance from supervenience and uses that distinction to criticize R. M. Hare’s account of the logic of moral judgement in terms of his notion of universalizability. It considers the strengths and weaknesses of Ross’s novel notion of a prima facie duty and the distinction between prima facie duty and duty proper. And it argues that where one action’s rightness results from its having certain properties, it does not follow that all actions with those properties will be right, because other cases may have further properties acting as ‘defeaters’.
On Knowing One’s Reason
Authors: Dancy Jonathan
Published: August 2021

This chapter is about the question whether one can act for the reason that p when one does not know that p. A negative answer to this question has been promoted by Unger, Hornsby, Hyman, and others, suggesting that the picture of motivation presented in my Practical Reality is not sufficiently respectful of the important differences between acting in the light of knowledge and acting in the light of mere belief, justified or otherwise. In responding to these criticisms, this paper revisits various themes from that book, in particular the non-factivity of reasons-explanations, and certain changes to the views expressed there are accepted.
Prichard on Causing a Change
Authors: Dancy Jonathan
Published: August 2021

This paper starts by considering an interesting argument of H. A. Prichard’s against the view that to act is to cause a change; the argument is that causing is not an activity. The argument is important because of the recent emergence of an ‘agent-causation’ view according to which actions are the causing of changes by agents. The author suggests a way of responding to Prichard’s argument, and then, profiting from one of his own conclusions, turns to consider the relation between neurophysiological changes and the causation of bodily movement by the agent. The paper makes a suggestion about the proper way to understand the relation between the neurophysiological changes, the bodily movements and the action.
Representationalism and Panpsychism
Authors: Tye Michael
Published: August 2021

A solution is offered to the paradox presented in Chapter 1. This solution requires us to embrace a qualified form of panpsychism for consciousness, or rather for a key element of consciousness I call “consciousness*”. Consciousness, I claim, is inherently representational and did indeed evolve. This is not true for consciousness*. Three problems are discussed for the hybrid view I develop: the problem of undirected consciousness; the problem of combination; and the problem of tiny psychological subjects. Solutions are offered for each of these problems. The final section of the chapter takes up the question of the causal efficacy of consciousness.
Policing the Borders Within
Authors: Aliverti Ana
Published: August 2021

Policing the Borders Within offers an in-depth, comprehensive exploration of the everyday working of inland border controls in Britain informed by extensive empirical material explored through the lens of wide-ranging interdisciplinary debates. In particular, this book examines afresh the relationship between policing, borders, and social order through the lens of migration policing. By charting this new landscape of everyday contemporary policing, the book’s main goal is to advance understanding of novel forms of law enforcement in a global age. These new forms of collaboration direct attention to the way in which front-line enforcement agents through their everyday work recreate the border, and not just enforce it. As the book argues, the emphasis on borders and migration controls and the growing importance of it within inland everyday policing is a symptom of the new demands and challenges facing the state in exercising authority in a fast-moving, interconnected world, and its attempt to offer a semblance of order. Such challenges result in practice in the random, capricious, informal, and arbitrary operation of power, which relies on non-rational, magic-like elements to solve policing problems. Through an ethnography of the worlds of police and immigration officers, the book dissects the ethical, political, legal, and social dilemmas, tensions, and contradictions posed by the task of maintaining order in a deeply unequal globalized world. The new impetus to police migration is an insightful entry point to understanding law enforcement in a global age.
Immigration Political Games (and Their Bruises)
Authors: Aliverti Ana
Published: August 2021

This chapter places the work of immigration officers within the broader politics of immigration in the UK. Front-line staff operate in a charged and polarizing environment, and are required to traverse this complex political arena in their daily shifts. Their work is laid open to politics in their daily work like no other area of government. Against the background of the Brexit vote, the chapter traces the growing salience of immigration in contemporary politics and the damaging effects of its electoral games in post-colonial Britain. Although such games have paid electoral dividends in the short term, they have also destroyed livelihoods. As if these games came full circle with the Windrush scandal, they had toxic institutional reverberations. The ambivalent and almost neurotic politics of immigration and its control which stirs imperial melancholia and profits from racialized public fears and anxieties, while shielding border work from view, brutalizes and demoralizes officers and tarnishes the department’s fragile legitimacy. It renders their everyday work hostage to the vagaries of politics and exposes them to the consequences of bad choices. As the chapter shows, immigration officers work to fulfil a fantasy, that of complete and perfect security, and bear the brunt of its disenchantments.
Writing at the Origin of Capitalism
Authors: Werlin Julianne
Published: August 2021

In the late sixteenth through seventeenth centuries, England simultaneously developed a national market and a national literary culture. In Writing at the Origin of Capitalism, Julianne Werlin describes how economic change in early modern England created new patterns of textual production and circulation with lasting consequences for English literature. Synthesizing research in book and media history, including investigations of manuscript and print, with Marxist historical theory, Werlin demonstrates that England’s transition to capitalism had a decisive impact on techniques of writing, rates of literacy, and modes of reception—and so on the form and style of texts. Individual chapters discuss the impact of market integration on linguistic standardization and the rise of a uniform English prose; the growth of a popular literary market alongside a national market in cheap commodities; and the decline of literary patronage with the monarchy’s loosening grip on trade regulation, among other subjects. Peddlers’ routes and price integration, monopoly licenses and bills of exchange, all prove vital for understanding early modern English writing. Each chapter reveals how books and documents were embedded in wider economic processes and, as a result, how the origin of capitalism constituted a revolutionary event in the history of English literature.
English Literature Abroad
Authors: Werlin Julianne
Published: August 2021

Beginning in the seventeenth century, English literary authors began to be printed and read in translation in European vernaculars. This chapter traces the relationship between capitalist England’s emergence as an international commercial and colonial power and the circulation of English literature on the Continent. Taking the career of John Milton as a case study, it argues that the English Revolution marked a turning point in England’s political and economic influence, and as a direct result, in the reception of its literature. By the end of the seventeenth century, England’s capitalist development enabled vernacular writers such as Milton, Shakespeare, and Bacon to enter the European literary canon.
Environmental factors affecting chytrid (Chytridiomycota) infection rates on Planktothrix agardhii
Authors: McKindles Katelyn M , Manes Makayla A , McKay R Michael , Davis Timothy W , Bullerjahn George S
Published: August 2021

Planktothrix agardhii dominates the cyanobacterial harmful algal bloom biomass in Sandusky Bay, Lake Erie (USA) from May until September. This filamentous cyanobacterium known parasites including the chytrid fungal species Rhizophydium sp. C02, which was previously isolated from this region. The purpose of our work has been to establish how parasitic interactions affect Planktothrix population dynamics during a bloom event. Samples analyzed from the 2015 to 2019 bloom seasons using quantitative PCR investigate the spatial and temporal prevalence of chytrid infections. Abiotic factors examined in lab include manipulating temperature (17–31°C), conductivity (0.226–1.225 mS/cm) and turbulence. Planktothrix-specific chytrids are present throughout the bloom period and are occasionally at high enough densities to exert parasitic pressure on their hosts. Temperatures above 27.1°C in lab can inhibit chytrid infection, indicating the presence of a possible upper thermal refuge for the host. Data suggest that chytrids can survive conductivity spikes in lab at levels three-fold above Sandusky Bay waters if given sufficient time (7–12 days), whereas increased turbulence in lab severely inhibits chytrid infections, perhaps due to disruption of chemical signaling. Overall, these data provide insights into the environmental conditions that inhibit chytrid infections during Planktothrix-dominated blooms in temperate waters.
Induced senescence of healthy nucleus pulposus cells is mediated by paracrine signaling from TNF‐α–activated cells
Authors: Ashraf Sajjad , Santerre Paul , Kandel Rita
Published: August 2021

Intervertebral disc degeneration is an irreversible process associated with accumulation of senescent nucleus pulposus (NP) cells. This study investigates the hypothesis that Tumor necrosis factor‐α (TNF‐α)–treated senescent NP cells propagate senescence of neighboring healthy cells via a paracrine effect that involves p‐Stat3 signaling and the cytokine interleukin‐6 (IL‐6). NP cells isolated from bovine caudal intervertebral disc (IVD) were treated with TNF‐α to induce senescence which was confirmed by demonstrating upregulation of senescence‐associated β‐galactosidase and p16. This was correlated with downregulation of NP‐associated markers, Aggrecan, Col2A1, and Sox9. Direct contact and non‐contact co‐culture of healthy and senescent cells showed that TNF‐α–treated cells increased the senescence in healthy cells via a paracrine effect. The senescent cells have a secretory phenotype as indicated by increased gene and protein levels of IL‐6. Phosphorylated Signal Transducer and Activator of Transcription 3 (pStat3) levels were also high in treated cells and appeared to upregulate IL‐6 as inhibition of Stat3 phosphorylation by StatticV downregulated IL‐6 mRNA expression in cells and protein levels in the culture media. All trans retinoic acid, an IL‐6 inhibitor, also decreased the secretion of IL‐6 and reduced the paracrine effect of senescent cells on healthy cells. Decreased pStat3 levels and inhibition of IL‐6 secretion did not fully restore NP gene expression of Col2A1 but importantly, appeared to cause senescent cells to undergo apoptosis and cell death. This study demonstrated the paracrine effect of senescent NP cells which involves Stat3 and IL‐6 and may explain why senescent NP cells accumulate in IVD with age. The role of pSTAT3 and IL‐6 in mediating NP senescence requires further study as it may be a novel strategy for modulating the senescent‐inducing effects of TNF‐α.
Translocation of LSR from tricellular corners causes macropinocytosis at cell–cell interface as a trigger for breaking out of contact inhibition
Authors: Kohno Takayuki , Konno Takumi , Kikuchi Shin , Kondoh Masuo , Kojima Takashi
Published: August 2021

Withdrawal from contact inhibition is necessary for epithelial cancer precursor cells to initiate cell growth and motility. Nevertheless, little is understood about the mechanism for the sudden initiation of cell growth under static conditions. We focused on cellular junctions as one region where breaking out of contact inhibition occurs. In well‐differentiated endometrial cancer cells, Sawano, the ligand administration for tricellular tight junction protein LSR, which transiently decreased the robust junction property, caused an abrupt increase in cell motility and consequent excessive multilayered cell growth despite being under contact inhibition conditions. We observed that macropinocytosis essentially and temporarily occurred as an antecedent event for the above process at intercellular junctions without disruption of the junction apparatus but not at the apical plasma membrane. Collectively, we concluded that the formation of macropinocytosis, which is derived from tight junction‐mediated signaling, was triggered for the initiation of cell growth in static precancerous epithelium.
CE: Reimagining Injurious Falls and Safe Mobility
Authors: Hendrich Ann L.
Published: August 2021

Injurious falls remain among the most common, dangerous, and costly adverse events in hospitals, despite the widespread implementation of fall prevention programs. Many current health care system policies and nursing practices oversimplify fall prevention by focusing on limiting the person's mobility and making the environment safer, or simply documenting a fall risk score. But most falls are caused by factors intrinsic to that individual; merely limiting their mobility can increase preventable hospital complications and readmissions, and still leaves them at risk for falls. This article proposes a new approach to reducing injurious falls in older adults—one grounded in evidence-based protocols known to positively impact the health of older adults. The approach, called by the acronym ERA—Electronic health record integration, Risk factors that matter, Assessment and care plans—allows nurses to use a validated fall risk assessment tool to reframe fall risk factors as part of the comprehensive care plan, and to map modifiable risk factors to interventions that address the underlying causes of falls and promote safer mobility. The ERA approach can help nurses use their time more effectively by focusing on targeted actions that improve patient outcomes, working in coordination with an interprofessional, cross-continuum care team.
Containment methods for incontinence
Authors: Doty Sherry Keck , Engels Dawn
Published: August 2021

Read about evidence-based nursing care for urine and stool collection to improve quality of life, promote independence, and reduce complications.
Establishing Age-calibrated Normative PROMIS Scores for Hand and Upper Extremity Clinic
Authors: Yedulla Nikhil R. , Wilmouth Carson T. , Franovic Sreten , Hazime Alaa A. , Hudson Jared T. , Day Charles S.
Published: August 2021

Background:

The purpose of our study is to investigate differences in normative PROMIS upper extremity function (PROMIS-UE), physical function (PROMIS-PF), and pain interference (PROMIS-PI) scores across age cohorts in individuals without upper extremity disability.

Methods:

Individuals without upper extremity disability were prospectively enrolled. Subjects were administered PROMIS-UE, PROMIS-PF, and PROMIS-PI forms. Retrospective PROMIS data for eligible subjects were also utilized. The enrolled cohort was divided into age groups: 20–39, 40–59, and 60–79 years old. ANOVA, ceiling and floor effect analysis, and kurtosis and skewness statistics were performed to assess PROMIS scores trends with age.

Results:

This study included 346 individuals. In the 20–39 age group, mean PROMIS scores were 56.2 ± 6.1, 59.8 ± 6.9, and 43.1 ± 6.7 for PROMIS-UE, PROMIS-PF, and PROMIS-PI, respectively. In the “40–59” age group, mean PROMIS computer adaptive test scores were 53.3 ± 7.5, 55.3 ± 7.6, and 46.6 ± 7.8 for PROMIS-UE, PROMIS-PF, and PROMIS-PI, respectively. In the 60–79 age group, mean PROMIS scores were 48.4 ± 7.6, 48.5 ± 5.6, and 48.7 ± 6.9 for PROMIS-UE, PROMIS-PF, and PROMIS-PI, respectively. Differences in mean PROMIS scores were significant across all PROMIS domains and age cohorts (P < 0.001).

Conclusion:

Younger individuals without hand or upper extremity disability show higher normative PROMIS-UE and PROMIS-PF scores and lower PROMIS-PI scores, indicating greater function and less pain than older counterparts. A universal reference PROMIS score of 50 appears suboptimal for clinical assessment and decision-making in the hand and upper extremity clinic.
Time-of-Year Variation in Intraocular Pressure
Authors: Morettin Christina E. , Roberts Daniel K. , Newman Tricia L. , Yang Yongyi , McMahon Janice M. , Roberts Mary Flynn , Teitelbaum Bruce A. , Winters Janis E.
Published: August 2021

Précis:

In this study conducted in Chicago, IL, intraocular pressure (IOP) level was found to have a subtle, but measurable, annual pattern. Reasonable evidence is presented for a time-of-year variation in IOP. Adequate numbers of subjects must be studied to detect this small variation.

Purpose:

The aim was to investigate the relationship between IOP and time of year.

Methods:

During a separate investigation, patients from 2011 to 2018 (dataset A, N=3041) in an urban, academic facility in Chicago, IL received an examination that included Goldmann applanation tonometry. Regression analyses assessed the relationship between time of year and IOP. Two additional datasets, 1 collected in a similar manner during 1999 and 2002 (dataset B, N=3261) and another consisting of all first visits during 2012 and 2017 (dataset C, N=69,858), were used to confirm and further investigate trends.

Results:

For dataset A, peak mean IOP occurred in December/January (15.7±3.7/15.7±3.8 mm Hg) and lowest in September (14.5±3.1 mm Hg). The analysis suggested conventional quarterly analysis (January to March, etc.) can conceal time-of-year relationships because of inadequate statistical power and timing of IOP variation. Multiple linear regression analysis, with a November-to-October reordering, detected an annual, downward IOP trend (P<0.0001). Analysis of dataset B confirmed this trend (P<0.001). Fourier analysis on datasets A and B combined supported a 12-month IOP cycle for right/left eyes (P=0.01/P=0.005) and dataset C provided stronger evidence for an annual periodicity (P<0.0001). Harmonics analysis of dataset C showed a repeating pattern where IOP trended downward around April, and then back upward around October.

Conclusions:

This analysis strongly supports a demonstrable annual, cyclical IOP pattern with a trough to peak variation of ≈1 mm Hg, which has a seasonal relationship.
Long-term cumulative incidence of metachronous advanced colorectal neoplasia after colonoscopy and a novel risk factor: a cohort study
Authors: Omata Fumio , Deshpande Gautam A. , Suzuki Hidekazu , Hayashi Kuniyoshi , Ishii Naoki , Matoba Kohei , Ohmuro Akemi , Rai Fumie , Takashima Misako , Fukuda Katsuyuki , Masuda Katsunori , Kumakura Yasuhisa
Published: August 2021

Background and aim

Long-term cumulative incidence of and risk factors for metachronous advanced colorectal neoplasia, including both advanced colorectal adenoma (≥10 mm, or with villous or high-grade dysplasia) and colorectal cancer, are critical for surveillance strategies. The aim of this study was to determine the cumulative incidence of metachronous advanced colorectal neoplasia and its risk factors.

Methods

A retrospective cohort study was conducted on 6720 consecutive individuals who underwent general health check-ups and colonoscopy. Colorectal adenomas at initial colonoscopy were categorized as low-risk (1–2 small [<10 mm] tubular adenomas) or high-risk adenoma (≥3 tubular adenomas of any size; at least one adenoma ≥10 mm; or villous adenoma or adenoma with high-grade dysplasia). Kaplan–Meier estimates and hazard ratio by Cox-proportional hazard regression were calculated.

Results

The cumulative incidence (95% confidence interval [CI]) of metachronous advanced colorectal neoplasia at 5 and 10 years was 5.7% [4.6–7.1], and 11% [8.9–14] in the low-risk adenoma group, and 10% [8.6–13], and 17% [14–21] in high-risk adenoma group, respectively. Adjusted hazard ratio [95% CI] of low-risk adenoma (vs. no colorectal adenoma), high-risk adenoma (vs. no colorectal adenoma), current smoking and positive fecal immunochemical test were 1.34 [1.04–1.74], 1.94 [1.48–2.55], 1.55 [1.2–2.02] and 1.69 [1.35–2.1], respectively. Adjusted hazard ratio [95% CI] of positive fecal immunochemical test was 1.88 [1.29–2.74] in those with normal colonoscopy.

Conclusions

Both low-risk and high-risk adenomas confer substantial risk for metachronous advanced colorectal neoplasia at 10 years. Positive fecal immunochemical test was a significant risk factor for metachronous advanced colorectal neoplasia despite normal colonoscopy.
Prediction of high-risk esophageal varices in patients with compensated cirrhosis using albumin-bilirubin-platelet score
Authors: Abd elbaser Elsayed Saad , Sharaf Ahmed Lotfy , Farag Alaa A.
Published: August 2021

Background

Despite the fact that endoscopy is the gold standard for screening of high-risk varices (HRVs) in patients with compensated cirrhosis, it is invasive, costly and not necessary for all patients. So, noninvasive tests can replace endoscopy. We aimed at evaluating the albumin-bilirubin-platelet (ALBL-PLT) score as a noninvasive test in predicting HRVs in compensated cirrhotic patients versus Baveno VI and extended Baveno VI criteria.

Methods

patients with compensated cirrhosis (n = 204) were included. Laboratory parameters, esophagogastroduodenoscopy (EGD) and liver stiffness measurement by transient elastography were done. Classification of patients according to the status of HRVs was done. We compared both groups on the basis of ALBL-PLT score, Baveno VI and extended Baveno VI criteria.

Results

Among the total patients, 96/204 (47%) patients had HRVs. They have higher liver stiffness measurement than those without HRVs (33 ± 13.1 versus 19.3 ± 8.25, CI, −19.94, −7.31, P value <0.001). Also, all HRVs patients have an ALBL-PLT score of more than 3. The area under the receiver operating characteristic curve for the ALBL-PLT score is higher than that for Baveno VI and extended Baveno VI criteria (0.894 versus 0.722 and 0.792, respectively).

Conclusion

ALBL-PLT score of more than three has a good predictive value in predicting HRVs among compensated cirrhotic patients.
Ustekinumab concentrations shortly after escalation to monthly dosing may identify endoscopic remission in refractory Crohn’s disease
Authors: Hanžel Jurij , Koželj Matic , Špes Hlastec Ana , Kurent Tina , Sever Nejc , Zdovc Jurij , Smrekar Nataša , Novak Gregor , Štabuc Borut , Grabnar Iztok , Drobne David
Published: August 2021

Objectives

Some patients with Crohn’s disease do not achieve remission with the approved maintenance dosing of ustekinumab every 8 weeks, possibly due to insufficient drug exposure. We aimed to study the exposure–response relationship for endoscopic remission and biomarker normalization with ustekinumab dose escalation to every 4 weeks.

Methods

Out of 135 consecutive patients, 44 with active Crohn’s disease despite standard maintenance dosing [at least one of C-reactive protein (CRP) >5 mg/L, fecal calprotectin >100 mg/kg, simple endoscopic score (SES) for Crohn’s disease >3] underwent dose escalation to every 4 weeks. Subsequent endoscopic remission (SES-CD ≤3 without ulceration) and biomarker normalization were compared against ustekinumab concentrations.

Results

Dose escalation led to endoscopic remission in 28.6% (8/28), CRP normalization 29.2% (7/24) and fecal calprotectin normalization 51.7% (15/29) of patients. Ustekinumab concentrations after escalation were higher in patients with endoscopic remission (6.90 vs. 4.29 mg/L; P = 0.025) and fecal calprotectin normalization (6.65 vs. 3.74 mg/L; P = 0.001). A threshold of 6.00 mg/L identified endoscopic remission [area under the receiver operating curve (AUROC): 0.775; 95% confidence interval (CI), 0.551–0.999), a threshold of 4.40 mg/L (AUROC 0.755; 95% CI, 0.545–0.964) two months after escalation identified patients with fecal calprotectin normalization at the end of follow-up. Concentrations <3.5 mg/L after escalation precluded endoscopic remission or biomarker normalization.

Conclusion

Endoscopic remission was associated with higher ustekinumab concentrations after dose escalation. Patients with concentrations <3.5 mg/L after dose escalation are unlikely to achieve endoscopic remission or biomarker normalization.
Comparison of long-term outcomes of balloon angioplasty with or without stent placement for hepatic vein type Budd-Chiari syndrome
Authors: Sun Xuedong , Zhang Jinlong , Duan Feng , Wang Maoqiang
Published: August 2021

Purpose

To compare percutaneous transluminal balloon angioplasty (PTBA) alone with PTBA plus stent placement for Budd-Chiari syndrome (BCS) patients with short-segmental obstruction of hepatic vein.

Methods

Between May 2001 and December 2010, 91 hepatic vein type BCS patients (mean age, 32.8 ± 10.8; M:F ratio 50:41) were included and divided into two groups (PTBA alone, as group A, n = 48; PTBA plus stent, as group B, n = 43). The incidence of restenosis, long-term patency, and survival were evaluated.

Results

All 91 patients were successfully treated with hepatic vein recanalization. During follow-up period (median 161 months, range: 84–234), group B had a significantly higher proportion of hepatic vein restenosis (56%, 24/43) than group A (33%, 16/48; P < 0.05). Cumulative primary patency rates at 1, 5, 10, 15 years were 96%, 81%, 69%, 65% and 91%, 60%, 47%, 47% in group A and group B, respectively (log-rank P < 0.05). Secondary technical success rates of target hepatic vein were 93% and 57% in group A and group B, respectively (P < 0.05). Clinical complete response rates were 94% and 86% in group A and group B, respectively (P > 0.05). The 15-year cumulative survival rates were 98% and 95% in group A and group B, respectively (P > 0.05). Major procedure-related complications occurred in 3 (3%) patients (1 in group A, 2 in group B).

Conclusions

Hepatic vein recanalization is safe and efficient for hepatic vein type BCS patients with hepatic vein short segmental obstruction. Restenosis after hepatic vein stenting is more common and difficult to manage than that after hepatic vein balloon angioplasty alone.
Editorial: Disparities in transplantation access and outcomes: mind the gap!
Authors: Martins Paulo N. , Kim Irene K.
Published: August 2021

Organ transplantation still remains a problem of supply and demand and presents multiple ethical challenges to our society. Despite numerous targeted interventions and policy reforms, women, underrepresented minorities and patients with low socioeconomic status (SES) continue to have unequal access to transplant. The purpose of this special edition is to highlight disparities in access to transplantation and posttransplant outcomes. Acknowledging that these disparities exist is the first step toward interventions aimed at mitigating this long-standing inequity. This issue provides 10 articles that give the background and summarize relevant literature describing these disparities and identify potential areas of intervention. Most of the data relates to the United States but may reflect patterns encounter in most societies. Each manuscript was written by leaders of international teams in the field of patient advocacy, public health or outcome research in transplantation.
Amyotrophic lateral sclerosis is a systemic disease: peripheral contributions to inflammation-mediated neurodegeneration
Authors: Appel Stanley H. , Beers David R. , Zhao Weihua
Published: August 2021

Purpose of review

Neuroinflammation is an important mediator of the pathogenesis of disease in amyotrophic lateral sclerosis (ALS). Genetic mutations such as C9orf72 have begun to define the numerous cell autonomous pathways that initiate motor neuron injury. Yet, it is the signalling to surrounding glia and peripherally derived immune cells that initiates the noncell autonomous inflammatory process and promotes self-propagating motor neuron cell death. The purpose of this review is to explore the systemic immune/inflammatory contributions to the pathogenesis of ALS: what are the peripheral pro-inflammatory signatures, what initiates their presence and do they represent potential therapeutic targets.

Recent findings

In ALS, motor neuron cell death is initiated by multiple cell autonomous pathways leading to misfolded proteins, oxidative stress, altered mitochondria, impaired autophagy and altered RNA metabolism, which collectively promote noncell autonomous inflammatory reactivity. The resulting disease is characterized by activated microglia and astrocytes as well as peripherally derived pro-inflammatory innate and adaptive immune cells. In this unrelenting disorder, circulating blood monocytes and natural killer cells are pro-inflammatory. Furthermore, regulatory T lymphocytes are dysfunctional, and pro-inflammatory cytokines and acute phase proteins are elevated.

The collective dysregulation of cells and cytokines in patients with ALS accurately reflect increased disease burdens, more rapid progression rates and reduced survival times, reinforcing the concept of ALS as a disorder with extensive systemic pro-inflammatory responses. These increased systemic pro-inflammatory immune constituents provide potentially meaningful therapeutic targets.
TMCC2 Associates with Alzheimer’s Disease Pathology in the Human Brain
Authors: Hopkins Paul C. R. , Troakes Claire , King Andrew , Tear Guy
Published: August 2021

Transmembrane and Coiled-Coil 2 (TMCC2) is a protein that forms complexes with both apolipoprotein E (apoE) and the amyloid protein precursor (APP), two proteins central to the etiology of Alzheimer’s disease (AD). Here we have carried out the first investigation of TMCC2 expression in the human brain, where TMCC2 immunoreactivity is primarily neuronal. We also examined TMCC2 localization in late onset AD brains,early onset AD cases bearing a mutation in APP, and in Down syndrome cases. TMCC2 immunoreactivity is closely associated with APP immunoreactivity in both control and AD cases. In all AD cases examined, TMCC2 associated with dense core senile plaques and adjacent dystrophic neurites, but not with amyloid surrounding the core, nor with diffuse amyloid plaques or neurofibrillary tangles. In Down syndrome, we found dystrophic neurites in senile plaques that were positive for amyloid and TMCC2, but not for APP, in addition to the APP- and TMCC2-positive dense cores. Western blot analysis revealed TMCC2 exists as at least three protein isoforms. The relative abundance of the isoforms varies in the temporal gyrus and cerebellum, the relative proportions of which were influenced by APOE and/or dementia status.

Taken together, these observations are consistent with the evolutionarily conserved interactions between APP and TMCC2 and suggest cooperation betweenTMCC2 and APP in the normal and AD brain. These findings thus support a role for TMCC2 as a mediator of the impact of apoE on AD pathogenesis.
Combining Plasma Extracellular Vesicle Let-7b-5p, miR-184 and Circulating miR-22-3p Levels for NSCLC Diagnosis and for Predicting Drug Resistance
Authors: Vadla G. P. , Daghat B. , Garcia A. , Perez G. , Ahmad V. , Patterson N. , Manjunath Y. , Kaifi J.T. , Li G. , Chabu C.Y.
Published: August 2021

Low-dose computed tomography (LDCT) Non-Small Cell Lung (NSCLC) screening is associated with high false-positive rates, leading to unnecessary expensive and invasive follow ups. There is a need for minimally invasive approaches to improve the accuracy of NSCLC diagnosis. Plasma extracellular vesicle (EV) and circulating microRNA (miRNA) have been proposed as cancer screening biomarkers. However, the identification of highly sensitive and broadly predictive core miRNA signatures remains a challenge. Also, how these systemic and diverse miRNAs impact cancer drug response is not well understood. Using an integrative approach, we examined plasma EV and circulating miRNA isolated from NSCLC patients versus screening controls with a similar risk profile. We found that combining EV (Hsa-miR-184, Let-7b-5p) and circulating (Hsa-miR-22-3p) miRNAs abundance robustly discriminates between NSCLC patients and high-risk cancer-free controls. Diagnosed NSCLC patients harboring sensitizing mutations in epidermal growth factor receptor EGFR (T790M, L578R) are treated with Osimertinib, a potent tyrosine kinase inhibitor (TKI). Nearly all patients develop TKI resistance via complex mechanisms and progress. We found that Hsa-miR-22-3p, Hsa-miR-184, and Let-7b-5p functionally converge on WNT/βcatenin and mTOR/AKT signaling axes, known cancer therapy resistance signals. Targeting Hsa-miR-22-3p and Hsa-miR-184 desensitized EGFR-mutated (T790M, L578R) NSCLC cells to Osimertinib. These findings suggest that the expression levels of circulating hsa-miR-22-3p combined with EV hsa-miR-184 and Let-7b-5p levels potentially define a core biomarker signature for improving the accuracy of NSCLC diagnosis. Importantly, these biomarkers have the potential to enable prospective identification of patients who are at risk of responding poorly to Osimertinib alone but likely to benefit from Osimertinib/AKT blockade combination treatments.
Ten Ostreobium (Ulvophyceae) strains from Great Barrier Reef corals as a resource for algal endolith biology and genomics
Authors: Pasella Marisa M. , Lee Ming-Fen Eileen , Marcelino Vanessa R. , Willis Anusuya , Verbruggen Heroen
Published: August 2021

Ostreobium is a genus of siphonous green algae that lives as an endolith in carbonate substrates under extremely limited light conditions and has recently been gaining attention due to its roles in reef carbonate budgets and its association with reef corals. Knowledge about this genus remains fairly limited due to the scarcity of strains available for physiological studies. Here, we report on 10 strains of Ostreobium isolated from coral skeletons from the Great Barrier Reef. Phenotypic diversity showed differences in the gross morphology and in few structures. Phylogenetic analyses of the tufA and rbcL put the strains in the context of the lineages identified previously through environmental sequencing. The chloroplast genomes of our strains are all around 80k bp in length and show that genome structure is highly conserved, with only a few insertions (some containing putative protein-coding genes) differing between the strains. The addition of these strains from the Great Barrier Reef to our toolkit will help develop Ostreobium as a model species for endolithic growth, low-light photosynthesis and coral-algal associations.
pyFoldX: enabling biomolecular analysis and engineering along structural ensembles
Authors: Radusky Leandro G. , Serrano Luis
Published: August 2021

Recent years have seen an increase in the number of structures available, not only for new proteins but also for the same protein crystallized with different molecules and proteins. While protein design software have proven to be successful in designing and modifying proteins, they can also be overly sensitive to small conformational differences between structures of the same protein. To cope with this, we introduce here pyFoldX, a python library that allows the integrative analysis of structures of the same protein using FoldX, an established forcefield and modeling software. The library offers new functionalities for handling different structures of the same protein, an improved molecular parametrization module, and an easy integration with the data analysis ecosystem of the python programming language.

Availability and implementation

pyFoldX is an open-source library that uses the FoldX software for energy calculations and modelling. The latter can be downloaded upon registration in http://foldxsuite.crg.eu/ and is free of charge for academics. Full details on installation, tutorials covering the library functionality, and the scripts used to generate the data and figures presented in this paper are available at https://github.com/leandroradusky/pyFoldX.
Leptin Signalling in the Ovary of Diet-Induced Obese Mice Regulates Activation of Nod-Like Receptor Protein 3 Inflammasome
Authors: Adamowski Marek , Wołodko Karolina , Oliveira Joana , Castillo-Fernandez Juan , Murta Daniel , Kelsey Gavin , Galvão António M.
Published: August 2021

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Obesity leads to ovarian dysfunction and the establishment of local leptin resistance. The aim of our study was to characterise levels of Nod-Like Receptor Protein 3 (NLRP3) inflammasome activation during obesity progression in the mouse ovaries and liver and test the putative role of leptin on its regulation. C57BL/6J mice were treated with equine chorionic gonadotropin (eCG) or human chorionic gonadotropin (hCG) for oestrous cycle synchronisation and ovaries collection. In diet-induced obesity (DIO) model, mice were fed chow diet (CD) or high fat diet (HFD) for 4 or 16 weeks (wk), whereas in hyperleptinemic model (LEPT), mice were injected with leptin for 16 days (16L) or saline (16C) and in the genetic obese leptin-deficient ob/ob (+/? and -/-) animals were fed CD for 4wk. Either ovaries and liver were collected, as well as cumulus cells (CCs) after superovulation from DIO and LEPT. In DIO protocol, protein expression of NLRP3 inflammasome components was increased in 4wk HFD, but decreased in 16wk HFD. Moreover LEPT and ob/ob models revealed NLRP3 and IL-1β upregulation in 16L and downregulation in ob/ob. Transcriptome analysis of CC showed common genes between LEPT and 4wk HFD modulating NLRP3 inflammasome. Moreover analysis in the liver showed upregulation of NLRP3 protein only after 16wk HFD, but also the downregulation of NLRP3 protein in ob/ob-/-. We showed the link between leptin signalling and NLRP3 inflammasome activation in the ovary throughout obesity progression in mice, elucidating the molecular mechanisms underpinning ovarian failure in maternal obesity.
A Synthetic Genetic Reversible Feynman Gate in a Single E.coli Cell and its Application in Bacterial to Mammalian Cell Information Transfer
Authors: Srivastava Rajkamal , Sarkar Kathakali , Bonnerjee Deepro , Bagh Sangram
Published: August 2021

Reversible computing is a nonconventional form of computing where the inputs and outputs are mapped in a unique one-to-one fashion. Reversible logic gates in single living cells have not been demonstrated. Here, we created a synthetic genetic reversible Feynman gate in a single E.coli cell. The inputs were extracellular chemicals, IPTG and aTc and the outputs were two fluorescence proteins EGFP and E2-Crimson. We developed a simple mathematical model and simulation to capture the essential features of the genetic Feynman gate and experimentally demonstrated that the behavior of the circuit was ultrasensitive and predictive. We showed an application by creating an intercellular Feynman gate, where input information from bacteria was computed and transferred to HeLa cells through shRNAs delivery and the output signals were observed as silencing of native AKT1 and CTNNB1 genes in HeLa cells. Given that one-to-one input-output mapping, such reversible genetic systems might have applications in diagnostics and sensing, where compositions of multiple input chemicals could be estimated from the outputs.
SIMPLE ASSAY FOR ADSORPTION OF PROTEINS TO THE AIR-WATER INTERFACE
Authors: Han Bong-Gyoon , Glaeser Robert M.
Published: August 2021

A rapid assay is described, based upon the Marangoni effect, which detects the formation of a denatured-protein film at the air-water interface (AWI) of aqueous samples. This assay requires no more than a 20 μL aliquot of sample, at a protein concentration of no more than1 mg/ml, and it can be performed with any buffer that is used to prepare grids for electron cryo-microscopy (cryo-EM). In addition, this assay provides an easy way to estimate the rate at which a given protein forms such a film at the AWI. Use of this assay is suggested as a way to pre-screen the effect of various additives and chemical modifications that one might use to optimize the preparation of grids, although the final proof of optimization still requires further screening of grids in the electron microscope. In those cases when the assay establishes that a given protein does form a sacrificial, denatured-protein monolayer, it is suggested that subsequent optimization strategies might focus on discovering how to improve the adsorption of native proteins onto that monolayer, rather than to prevent its formation. A second alternative might be to bind such proteins to the surface of rationally designed affinity grids, in order to prevent their diffusion to, and unwanted interaction with, the AWI.