bluuebunny/crossref_metadata_2025 huggingface dataset:
21. Equitable Orders
Authors: Virgo Graham
Published: September 2020

This chapter examines various other equitable remedies to illustrate the significant impacts of Equity on the remedial landscape of English law, particularly in a commercial context. It discusses the key principles that influence the equitable jurisdiction to make orders. These remedies include various types of injunction, including freezing orders, search orders, specific performance, rescission, and rectification. In each case the nature and function of the order is examined and the requirements for obtaining each order is identified. The chapter particularly focuses on the remedy of rescission to determine when the remedy should be available and how it operates. The chapter identifies various principles relating to the award of equitable orders and makes connections to other fundamental equitable principles which have been recognized throughout the book.
7. Creditors
Authors: Davies Paul
Published: September 2020

Because of limited liability, creditor protection has always been a feature of company law. Large creditors can contract ex ante for customised protection and the law facilitates this in various ways, notably by the creation of the floating charge. Non-adjusting creditors require the protection of mandatory rules, at least in some situations. Creditor protection in relation to companies in the vicinity of insolvency is now well established, not only through ‘wrongful trading’ but also via transaction invalidity rules and directors’ disqualification. For going-concern companies the emphasis is on rules restricting the shifting assets to shareholders via distributions and associated rules relating to the maintenance of capital.
Contract Law
Authors: McKendrick Ewan
Published: September 2020

Contract Law: Text, Cases, and Materials provides a complete guide to the subject of contract law. The book comprises a balance of 60% text to 40% cases and materials. Its clear explanations and analyses of the law provide support to students, while the extracts from cases and materials promote the development of essential case reading skills and allow for a more detailed appreciation of the practical workings of the law and of the best legal scholarship. Part I of the book examines the rules relating to the existence of an agreement (particularly offer and acceptance, uncertain and incomplete agreements, and consideration and promissory estoppel). Part II covers the terms of the contract, including implied terms, interpretation, boilerplate clauses, exclusion clauses, unfair terms in consumer contracts, and good faith. Part III examines topics such as mistake, misrepresentation, duress, undue influence, unconscionability, inequality of bargaining power, and frustration and force majeure. Part IV turns to breaches of contract and termination, damages, and specific performance. The last part, Part V, concentrates on third parties.
15. Good Faith
Authors: McKendrick Ewan
Published: September 2020

This chapter discusses the role of good faith in contract law, first analysing the decision in Walford v. Miles [1992] 2 AC 128, where it was held that an obligation to negotiate in good faith is not valid. It then examines the reasons that led to the decision and also explores its limits. Next, the chapter considers the arguments that have been advanced in support of the refusal of English law to recognize the validity of a doctrine of good faith and then turns to the arguments that have been advanced by those who support the recognition of a doctrine of good faith. It concludes by examining the development of a doctrine of good faith in the performance of contracts.
18. Duress
Authors: McKendrick Ewan
Published: September 2020

A contract can be set aside on the ground that it has been entered into under duress. This chapter presents cases illustrating the different forms of duress, namely duress of the person, duress of goods, and economic duress. The case-law establishes that there are two principal elements to a duress claim: (i) lack of consent/coercion of the will and (ii) the illegitimacy of the pressure exerted. The chapter examines the idea of ‘illegitimacy’, in particular whether a threat to breach a contract is always illegitimate and the scope of ‘lawful act’ duress.
25. Third Parties
Authors: McKendrick Ewan
Published: September 2020

This chapter examines the impact of a contract on third parties. It addresses two main questions: whether or not a third party can acquire any rights under the contract, and whether or not the contract can impose upon him obligations or liabilities. The general rule adopted by English law is that the contract creates rights and imposes obligations only between the parties to the contract: the third party thus neither acquires rights under the contract nor is he subject to liabilities. This general rule is known as the doctrine of privity of contract. The Contracts (Rights of Third Parties) Act 1999, however, provides a relatively simple mechanism by which contracting parties can confer upon a third party a right to enforce a term of their contract. The dominant philosophy that underpins the 1999 Act is one of freedom of contract and, this being the case, the success of the Act in practice will depend upon contracting parties themselves. The chapter examines the individual sections of the 1999 Act, the exceptions to the doctrine of privity that existed at common law and under various statutes prior to the enactment of the 1999 Act. The chapter concludes by considering the extent to which a third party can be subject to an obligation by a contract to which he is not a party.
6. The effects of EU law in the national legal systems
Authors: Bobek Michal
Published: September 2020

This chapter examines how EU law interacts with national legal systems. It first explains the default rules for the national application of EU law. It then focuses on three key principles: direct effect, indirect effect, and primacy. It considers requirements formulated with respect to procedures for the national enforcement of EU law and state liability for breaches of EU law. The chapter concludes with a case study, which illustrates the interplay between the rules and principles introduced in this chapter.
22. European consumer law
Authors: Howells Geraint
Published: September 2020

This chapter examines EU consumer law. It discusses the negative impact of EU law on national consumer protection rules; rules on information duties (including the duty to not mislead) and the right of withdrawal; rules establishing consumer expectations; rules on product safety and product liability; and rules on unfair terms and sale of goods. The chapter also covers EU legislation providing general substantive rights; enforcement of consumer protection rules; and consumers’ right of private redress.
7. Decision-Making and New Forms of Governance
Authors: Craig Paul , de Búrca Gráinne
Published: September 2020

All books in this flagship series contain carefully selected substantial extracts from key cases, legislation, and academic debate, providing students with a stand-alone resource. This chapter introduces the debate over new modes of decision-making and governance in the EU, and provides an account of the apparent shift towards greater use of these over time. The language of ‘new’ forms of governance in the EU refers to the move away from reliance on hierarchical modes towards more flexible modes as the preferred method of governing. A number of examples of new governance instruments and methods are provided, in particular the ‘new approach to harmonization’ and the ‘open method of coordination’. A number of other EU governance reform initiatives related to the new governance debate are also discussed, such as the subsidiarity and proportionality principles, the ‘better regulation’ initiative, and the Commission White Paper on Governance and its follow-up. The UK version contains a further section analysing issues of new governance in relation to the UK post-Brexit.
8. The Nature and Effect of EU Law: Direct Effect and Beyond
Authors: Craig Paul , de Búrca Gráinne
Published: September 2020

All books in this flagship series contain carefully selected substantial extracts from key cases, legislation, and academic debate, providing students with a stand-alone resource. This chapter discusses the doctrine of direct effect. In a broad sense direct effect means that provisions of binding EU law, which are sufficiently clear, precise, and unconditional to be considered justiciable, can be invoked and relied on by individuals before national courts. The legal effect of directives is complex. They have vertical but not horizontal direct effect. The ECJ has however crafted a growing number of qualifications to the proposition that directives do not have horizontal direct effect. The result is that directives can still have ‘legal effect’ on private parties in various ways through the principle of indirect effect/harmonious interpretation; incidental effect; fundamental rights; general principles of law; and where a regulation makes reference to a directive. The UK version contains a further section analysing issues concerning direct effect in relation to the UK post-Brexit.
17. Damages Actions and Money Claims
Authors: Craig Paul , de Búrca Gráinne
Published: September 2020

All books in this flagship series contain carefully selected substantial extracts from key cases, legislation, and academic debate, providing students with a stand-alone resource. Article 340 of the Treaty on the Functioning of the European Union (TFEU) governs compensation against the EU. It leaves the Court of Justice of the European Union with considerable room for interpretation, and directs it to consider the general principles common to the laws of the Member States. The key issue is the test for liability where losses are caused by EU acts that are illegal. The Court has fashioned different tests for cases where the challenged act is of a discretionary nature and for those where it is not. This chapter discusses the application of Article 340 in relation to discretionary and non-discretionary EU acts, official acts of Union servants, valid legislative acts, causation and damage, joint liability for the EU and Member States, contractual liability, and restitution. The UK version contains a further section analysing the relevance of Article 340 in relation to the UK post-Brexit.
27. Competition Law: Article 101
Authors: Craig Paul , de Búrca Gráinne
Published: September 2020

All books in this flagship series contain carefully selected substantial extracts from key cases, legislation, and academic debate, providing students with a stand-alone resource. EU competition law covers anti-competitive agreements between firms, abuse of a dominant position, and mergers. Article 101 TFEU is the principal vehicle for the control of anti-competitive agreements. This chapter examines its key features. These include: the meaning given to the terms agreement and concerted practice; the relationship between Article 101(1) and (3); the extent to which economic analysis does and should take place within Article 101(1); and the interpretation accorded to Article 101(3), including whether non-economic factors can be taken into account. The discussion then shifts to more detailed examination of vertical agreements, followed by an outline of the reform of the enforcement regime for Articles 101 and 102. The UK version contains a further section analysing issues concerning EU competition law and the UK post-Brexit.
4. Fundamental Rights
Authors: Schütze Robert
Published: September 2020

This chapter evaluates the European fundamental rights. Human rights constitutionally limit the exercise of all European Union competences—including its legislative competences. Three sources of European fundamental rights were subsequently developed: the ‘unwritten’ bill of rights in the form of general principles of European law; the European Convention on Human Rights (ECHR); and the EU Charter of Fundamental Rights. The chapter investigates these three bills of rights of the EU, beginning with the discovery of an ‘unwritten’ bill of rights in the form of general principles of European law. It then discusses possible structural limits to European human rights in the form of international obligations flowing from the United Nations Charter. The chapter also analyses the EU's ‘written’ bill of rights in the form of its Charter of Fundamental Rights. Finally, it explores the ECHR as an external bill of rights for the EU.
8. The Nature and Effect of EU Law: Direct Effect and Beyond
Authors: Craig Paul , Búrca Gráinne de
Published: September 2020

All books in this flagship series contain carefully selected substantial extracts from key cases, legislation, and academic debate, providing students with a stand-alone resource. This chapter discusses the doctrine of direct effect. In a broad sense direct effect means that provisions of binding EU law, which are sufficiently clear, precise, and unconditional to be considered justiciable, can be invoked and relied on by individuals before national courts. The legal effect of directives is complex. They have vertical but not horizontal direct effect. The ECJ has however crafted a growing number of qualifications to the proposition that directives do not have horizontal direct effect. The result is that directives can still have ‘legal effect’ on private parties in various ways through the principle of indirect effect/harmonious interpretation; incidental effect; fundamental rights; general principles of law; and where a regulation makes reference to a directive. The UK version contains a further section analysing issues concerning direct effect in relation to the UK post-Brexit.
22. Free Movement of Workers
Authors: Craig Paul , de Búrca Gráinne
Published: September 2020

All books in this flagship series contain carefully selected substantial extracts from key cases, legislation, and academic debate, providing students with a stand-alone resource. The free movement of workers is of central importance to the EU, in both economic and social terms. This is reflected in the legislation that fleshes out the basic rights contained in Article 45 and in the European Court of Justice’s consistently purposive interpretation of the Treaty Articles and legislation to achieve the EU’s objectives in this area. This chapter considers several central legal issues that arise in the context of the free movement of workers. These include the scope of Article 45, the meaning accorded to ‘worker’, the rights of intermediate categories such as ‘job-seeker’, the kinds of restrictions that states may justifiably impose on workers and their families; and the rights which family members enjoy under EU law. The UK version contains a further section analysing issues concerning free movement of workers between the EU and the UK post-Brexit.
2. The Historical Evolution of the International Community
Authors: Gaeta Paola , Viñuales Jorge E. , Zappalà Salvatore
Published: September 2020

This chapter traces the historical evolution of the international legal system, which is organized for analytical purposes in four major stages: from its gradual emergence (sixteenth–early seventeenth century) to the First World War; from the establishment of the League of Nations to the end of the Second World War (1919–1945); from the establishment of the United Nations to the end of the Cold War (1945–1989); and the last three decades since the end of the Cold War (1990–2020). The chapter emphasizes the European roots of international law but also the pressure it has faced since the 1960s to reflect the interests of developing and newly independent States. It also provides some basic historical elements and references to the growing literature on the history of international law, which are useful to understand the historical context of the material examined in subsequent chapters.
7. International Organizations
Authors: Gaeta Paola , Viñuales Jorge E. , Zappalà Salvatore
Published: September 2020

This chapter discusses the international legal personality of international organizations, illustrating the origins of the phenomenon, the evolution of such organizations over time, and the different types of organization. It goes on to consider the source and scope of their status and powers within the international legal order, inter alia, by focusing on the principle of speciality (or conferral) and the theory of implied powers. The chapter then deals with the problem of the recognition of immunities of international organizations and their personnel, as well as with the debate surrounding the rules which relate to their responsibility under international law.
9. Law-Making Processes
Authors: Gaeta Paola , Viñuales Jorge E. , Zappalà Salvatore
Published: September 2020

Custom and treaties constitute the two most important formal sources of international law, that are also envisaged in Article 38 of the ICJ Statute. In addition, Article 38 refers to general principles of law recognized in domestic systems. This chapter examines these three formal sources of international law as well as some others, in particular unilateral acts of States and binding decisions of international organizations. In addition, it discusses equity and soft law and examines some mechanisms of identification and development of international law, such as jurisprudence, doctrine, and codification.
12. International State Responsibility for Wrongful Acts
Authors: Gaeta Paola , Viñuales Jorge E. , Zappalà Salvatore
Published: September 2020

The chapter begins by discussing the history of the codification of the law of State responsibility. It then considers the current regulation of State responsibility, by distinguishing the ‘ordinary’ legal regime and the ‘aggravated’ State responsibility, and goes on to explore the main differences between the two regimes. It focuses on the elements of the internationally wrongful act, particularly on the attribution of conduct to a State and the relevance of fault and damage. In addition, it examines the circumstances which preclude wrongfulness and the consequences of the internationally wrongful act (with particular reference to the obligation to provide reparation).
19. The Repression of International Crimes
Authors: Gaeta Paola , Viñuales Jorge E. , Zappalà Salvatore
Published: September 2020

This chapter begins with an overview of international crimes, namely, offences entailing the personal criminal liability of the individuals concerned (as opposed to the responsibility of the State) under international law. International crimes include war crimes, crimes against humanity, genocide, torture, aggression, and terrorism. The discussion then turns to the prosecution and punishment by State courts, focusing on the grounds of criminal jurisdiction and in particular universal criminal jurisdiction. It ends with an overview of the prosecution and punishment by international criminal courts and tribunals, with an emphasis on the International Criminal Court, and with an assessment of the main problems besetting international criminal proceedings.
Loss ofAnks6leads to YAP deficiency and liver abnormalities
Authors: Airik Merlin , Schüler Markus , McCourt Blake , Weiss Anna-Carina , Herdman Nathan , Lüdtke Timo H , Widmeier Eugen , Stolz Donna B , Nejak-Bowen Kari N , Yimlamai Dean , Wu Yijen L , Kispert Andreas , Airik Rannar , Hildebrandt Friedhelm
Published: September 2020

ANKS6 is a ciliary protein that localizes to the proximal compartment of the primary cilium, where it regulates signaling. Mutations in the ANKS6 gene cause multiorgan ciliopathies in humans, which include laterality defects of the visceral organs, renal cysts as part of nephronophthisis and congenital hepatic fibrosis (CHF) in the liver. Although CHF together with liver ductal plate malformations are common features of several human ciliopathy syndromes, including nephronophthisis-related ciliopathies, the mechanism by which mutations in ciliary genes lead to bile duct developmental abnormalities is not understood. Here, we generated a knockout mouse model of Anks6 and show that ANKS6 function is required for bile duct morphogenesis and cholangiocyte differentiation. The loss of Anks6 causes ciliary abnormalities, ductal plate remodeling defects and periportal fibrosis in the liver. Our expression studies and biochemical analyses show that biliary abnormalities in Anks6-deficient livers result from the dysregulation of YAP transcriptional activity in the bile duct-lining epithelial cells. Mechanistically, our studies suggest, that ANKS6 antagonizes Hippo signaling in the liver during bile duct development by binding to Hippo pathway effector proteins YAP1, TAZ and TEAD4 and promoting their transcriptional activity. Together, this study reveals a novel function for ANKS6 in regulating Hippo signaling during organogenesis and provides mechanistic insights into the regulatory network controlling bile duct differentiation and morphogenesis during liver development.
Lipid Profiles in Patients With Ulcerative Colitis Receiving Tofacitinib—Implications for Cardiovascular Risk and Patient Management
Authors: Sands Bruce E , Colombel Jean-Frédéric , Ha Christina , Farnier Michel , Armuzzi Alessandro , Quirk Daniel , Friedman Gary S , Kwok Kenneth , Salese Leonardo , Su Chinyu , Taub Pam R
Published: September 2020

Background

Patients with ulcerative colitis (UC) are at elevated risk of cardiovascular disease vs the general population, despite a lower prevalence of traditional risk factors, including hyperlipidemia. Mechanistic studies in patients with rheumatoid arthritis and psoriasis suggest that tofacitinib restores serum lipids to preinflammation levels by reversing inflammation-induced cholesterol metabolism changes. We reviewed data on lipid levels and cardiovascular events, alongside recommendations for managing lipid levels during tofacitinib treatment in patients with UC, based on up-to-date expert guidelines.

Methods

Data were identified from a phase 3/open-label, long-term extension (OLE) tofacitinib UC clinical program (cutoff May 27, 2019). Literature was identified from PubMed (search terms “lipid,” “cholesterol,” “lipoprotein,” “cardiovascular,” “inflammation,” “atherosclerosis,” “tofacitinib,” “rheumatoid arthritis,” “psoriasis,” “inflammatory bowel disease,” “ulcerative colitis,” “hyperlipidemia,” and “guidelines”) and author knowledge. Data were available from 4 phase 3 clinical trials of 1124 patients with moderately to severely active UC who received ≥1 dose of tofacitinib 5 or 10 mg twice daily in induction (two identical trials), maintenance, and OLE studies (treatment duration ≤6.8 years; 2576.4 patient-years of drug exposure).

Results

In the OLE study, tofacitinib treatment was not associated with major changes from baseline in total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, total cholesterol/high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol, with lipid levels and ratios generally remaining stable over time. The major adverse cardiovascular events incidence rate was 0.26/100 patient-years (95% confidence interval, 0.11-0.54).

Conclusions

Lipid levels and ratios remained generally unchanged from baseline in the OLE study after tofacitinib treatment, and major adverse cardiovascular events were infrequent. Long-term studies are ongoing.

ClinicalTrials.gov identifiers

NCT01465763, NCT01458951, NCT01458574, NCT01470612
Assessing palliative care need in left ventricular assist device patients and heart transplant recipients
Authors: Strangl Felix , Ullrich Anneke , Oechsle Karin , Bokemeyer Carsten , Blankenberg Stefan , Knappe Dorit , Reichenspurner Herrmann , Bernhardt Alexander M , Barten Markus J , Rybczynski Meike
Published: September 2020

Objectives

Palliative care (PC) has gained rising attention in a holistic treatment approach to chronic heart failure (HF). It is unclear whether there is a need for PC in left ventricular assist device (LVAD) patients or heart transplant recipients.

Methods

In a cross-sectional explorative pilot study, outpatients after heart transplantation (HTx, n = 69) or LVAD implantation (n = 21) underwent screening for palliative care (PC) need and evaluation of symptom burden and psychological distress using tools that emanated from palliative cancer care.

Results

The ‘Palliative Care Screening Tool for Heart Failure Patients’ revealed scores of 4.3 ± 2.2 in HTx and 6.0 ± 2.1 in LVAD patients (max. 12 points, P = 0.003), indicating the need for PC (≥5 points) in 32% of HTx and 67% of LVAD patients. Symptom burden, as assessed by MIDOS (‘Minimal Documentation System for Palliative Care’) scores was substantial in both groups (4.9 ± 4.7 in HTx vs 6.6 ± 5.3 in LVAD, max. 30 points, P = 0.181). ‘Fatigue’, ‘weakness’ and ‘pain’ were the most frequent symptoms. Using the ‘Distress-Thermometer’, ‘clinically relevant’ distress was detected in 57% of HTx and 47% of LVAD patients (P = 0.445). In the PHQ-4 (‘4-Item Patient Health Questionnaire’), 45% of LVAD patients, compared to only 10% of HTx patients, reported mild symptoms of anxiety and depression.

Conclusions

Findings reveal substantial need for PC in LVAD patients and, to a lesser extent, in heart transplant recipients, suggesting that multi-disciplinary PC should be introduced into routine aftercare.
The Effects of Populist Identity Framing on Populist Attitudes Across Europe: Evidence From a 15-Country Comparative Experiment
Authors: Hameleers Michael , Schmuck Desirée , Schulz Anne , Wirz Dominique Stefanie , Matthes Jörg , Bos Linda , Corbu Nicoleta , Andreadis Ioannis
Published: September 2020

We investigate the effects of populist messages that (a) stress the centrality of “ordinary” people, (b) shift blame to the “corrupt” elites, or (c) combine people centrality and antielitist cues on 3 dimensions of populist attitudes: anti-elitism, homogeneous people, and popular sovereignty. We conducted an extensive 15-country experiment in which we manipulated populist communication as social identity frames (N = 7,271). Multilevel analyses demonstrate that messages stressing the centrality of the ordinary people activate all dimensions of populist attitudes. In contrast, anti-elite messages activate anti-elitism attitudes only for those individuals with lower levels of education and extreme positions on the ideological left–right spectrum. Our findings suggest that populist political communication plays a key role in activating populist attitudes across Europe.
Human factors and ergonomics systems approach to the COVID-19 healthcare crisis
Authors: Carayon Pascale , Perry Shawna
Published: September 2020

A human factors and ergonomics (HFE) systems approach offers a model for adjusting work systems and care processes in response to a healthcare crisis such as COVID-19. Using the Systems Engineering Initiative for Patient Safety (SEIPS) model of work system and patient safety, we describe various work system barriers and facilitators experienced by healthcare workers during the COVID-19 crisis. We propose a set of five principles based on this HFE systems approach related to novel pandemic: (i) deferring to local expertise, (ii) facilitating adaptive behaviors, (iii) enhancing interactions between system elements and levels along the patient journey, (iv) re-purposing existing processes and (v) encouraging dynamic continuous learning.
Comparative effects of two multispecies direct-fed microbial products on energy status, nutrient digestibility, and ruminal fermentation, bacterial community, and metabolome of beef steers
Authors: Ogunade Ibukun M , McCoun Megan , Idowu Modoluwamu D , Peters Sunday O
Published: September 2020

We examined the effects of two direct-fed microbials (DFM) containing multiple microbial species and their fermentation products on energy status, nutrient digestibility, and ruminal fermentation, bacterial community, and metabolome of beef steers. Nine ruminally cannulated Holstein steers (mean ± SD body weight: 243 ± 12.4 kg) were assigned to three treatments arranged in a triplicated 3 × 3 Latin square design with three 21-d periods. Dietary treatments were 1) control (CON; basal diet), 2) Commence (PROB; basal diet plus 19 g/d of Commence), and 3) RX3 (SYNB; basal diet plus 28 g/d of RX3). Commence and RX3 are both multispecies DFM products. From day 16 to 20 of each period, feed and fecal samples were collected daily to determine the apparent total tract digestibilities of nutrients using indigestible neutral detergent fiber method. On day 21 of each period, blood samples were collected for analysis of plasma glucose and nonesterified fatty acid. Ruminal contents were collected at approximately 1, 3, 6, 9, 12, and 18 h after feeding on day 21 for analysis of volatile fatty acids (VFA), lactate, ammonia-N concentrations, bacterial community, and metabolome profile. Total tract digestibilities of nutrients did not differ (P > 0.05) among treatments. Compared with CON, steers fed either supplemental PROB or SYNB had greater (P = 0.04) plasma glucose concentrations. Compared with CON, total ruminal VFA, propionate, isovalerate, and valerate concentrations increased (P ≤ 0.05) or tended to increase (P ≤ 0.10) with either supplemental PROB or SYNB, but were not different (P > 0.05) between PROB and SYNB. Compared with CON, PROB reduced (P ≤ 0.05) the relative abundance of Prevotella 1 and Prevotellaceae UCG-001 but increased (P ≤ 0.05) the relative abundance of Rikenellaceae RC9, Succinivibrionaceae UCG-001, Succiniclasticum, and Ruminococcaceae UCG-002. Supplemental SYNB decreased (P ≤ 0.05) the relative abundance of Prevotella 1 and Prevotellaceae UCG-001 but increased (P ≤ 0.05) the relative abundance of Prevotella 7, Succinivibrio, Succiniclasticum, and Ruminococcaceae UCG-014. Compared with CON, metabolome analysis revealed that some amino acids were increased (P ≤ 0.05) in steers fed PROB. This study demonstrated that, compared with CON, supplementation of either PROB or SYNB altered the ruminal bacterial community and metabolome differently; however, their effects on the ruminal VFA profile and energy status of the steers were not different from each other.
Wolbachia in Native Populations of Aedes albopictus (Diptera: Culicidae) From Yucatan Peninsula, Mexico
Authors: Puerta-Guardo Henry , Contreras-Perera Yamili , Perez-Carrillo Silvia , Che-Mendoza Azael , Ayora-Talavera Guadalupe , Vazquez-Prokopec Gonzalo , Martin-Park Abdiel , Zhang Dongjing , Manrique-Saide Pablo ,   UCBE-LCB Team, Palacio-Vargas Jorge , Pérez-Ojeda Javier , Navarrete-Carballo Juan , Marin Wilbert Bibiano , Barreiro Anuar Medina , Palacio-Vargas Jorge , Pérez-Ojeda Javier , Navarrete-Carballo Juan , Marin Wilbert Bibiano , Barreiro Anuar Medina
Published: September 2020

This study reports the results of a molecular screening for Wolbachia (Wb) infection in Aedes albopictus (Skuse) populations recently established in the Yucatan Peninsula, Mexico. To do so, collections of free-flying adults with BG traps and emerged adults from eggs after ovitrap field collections were performed in three suburban localities of the city of Merida, Yucatan. Overall, local populations of Ae. albopictus present a natural Wb infection rate of ~40% (18 of 45). Wb infection was detected in both field-collected adults (76.5%, 13 of 17) and eggs reared (17.8%, 5 of 28) and in 37.9% (11/29) of females and 43.7% (7/16) of male Ae. albopictus mosquitoes. An initial screening for Wolbachia strain typing showed that native Ae. albopictus were naturally coinfected with both wAlbA and wAlbB strains. The knowledge of the prevalence and diversity of Wolbachia strains in local populations of Aedes mosquitoes is part of the baseline information required for current and future Wolbachia-based vector control approaches to be conducted in Mexico.
Incident Type 2 Diabetes Duration and Cancer Risk: A Prospective Study in Two US Cohorts
Authors: Hu Yang , Zhang Xuehong , Ma Yanan , Yuan Chen , Wang Molin , Wu Kana , Tabung Fred K , Tobias Deirdre , Hu Frank B , Giovannucci Edward , Song Mingyang
Published: September 2020

Background

The influence of type 2 diabetes mellitus (T2D) duration on cancer incidence remains poorly understood.

Methods

We prospectively followed for cancer incidence 113 429 women in the Nurses’ Health Study (1978-2014) and 45 604 men in the Health Professionals Follow-up Study (1988-2014) who were free of diabetes and cancer at baseline. Cancer incidences were ascertained by review of medical records.

Results

In the multivariable-adjusted model incident, T2D was associated with higher risk of cancers in the colorectum, lung, pancreas, esophagus, liver, thyroid, breast, and endometrium. The pooled hazard ratios (HRs) ranged from 1.21 (95% confidence interval [CI] = 1.06 to 1.38) for colorectal cancer to 3.39 (95% CI = 2.24 to 5.12) for liver cancer. For both composite cancer outcomes and individual cancers, the elevated risks did not further increase after 8 years of T2D duration. The hazard ratio for total cancer was 1.28 (95% CI = 1.17 to 1.40) for T2D duration of 4.1-6.0 years, 1.37 (95% CI = 1.25 to 1.50) for 6.1-8.0 years, 1.21 (95% CI = 1.09 to 1.35) for 8.1-10.0 years, and 1.04 (95% CI = 0.95 to 1.14) after 15.0 years. In a cross-sectional analysis, a higher level of plasma C-peptide was found among participants with prevalent T2D of up to 8 years than those without T2D, whereas a higher level of HbA1c was found for those with prevalent T2D of up to 15 years.

Conclusions

Incident T2D was associated with higher cancer risk, which peaked at approximately 8 years after diabetes diagnosis. Similar duration-dependent pattern was observed for plasma C-peptide. Our findings support a role of hyperinsulinemia in cancer development.
Blending Probability and Nonprobability Samples with Applications to a Survey of Military Caregivers
Authors: Robbins Michael W , Ghosh-Dastidar Bonnie , Ramchand Rajeev
Published: September 2020

Probability samples are the preferred method for providing inferences that are generalizable to a larger population. However, in many cases, this approach is unlikely to yield a sample size large enough to produce precise inferences. Our goal here is to improve the efficiency of inferences from a probability sample by combining (or blending) it with a nonprobability sample, which is (by itself) potentially fraught with selection biases that would compromise the generalizability of results. We develop novel methods of statistical weighting that may be used for this purpose. Specifically, we make a distinction between weights that can be used to make the two samples representative of the population individually (disjoint blending) and those that make only the combined sample representative (simultaneous blending). Our focus is on weights constructed using propensity scores, but consideration is also given to calibration weighting. We include simulation studies that, among other illustrations, show the gain in precision provided by the convenience sample is lower in circumstances where the outcome is strongly related to the auxiliary variables used to align the samples. Motivating the exposition is a survey of military caregivers; our interest is focused on unpaid caregivers of wounded, ill, or injured US servicemembers and veterans who served following September 11, 2001. Our work serves not only to illustrate the proper execution of blending but also to caution the reader with respect to its dangers, as invoking a nonprobability sample may not yield substantial improvements in precision when assumptions are valid and may induce biases in the event that they are not.
Non-Pharmaceutical Interventions and Military Hygiene at the United States Military Academy between 1890 and 1910
Authors: Eslinger Melissa , Washington Michael A , Pekny Carissa , Nepa Natalie , Wickiser J Kenneth , Limbocker Ryan A , Shanks G Dennis
Published: September 2020

Introduction

Military installations are at increased risk for the transmission of infectious disease. Personnel who live and train on military installations live and train near one another facilitating disease transmission. An understanding of historical sanitation and hygiene can inform modern practices. This is especially pertinent considering the continuing rise of variants of infectious diseases, such as the recent pandemic of the 2019 severe acute respiratory syndrome coronavirus 2. In this article, we review the rise and decline of infectious disease at the United States Military Academy (USMA) during the period spanning 1890 through 1910, and the public health interventions used to combat disease spread.

Materials and Methods

Primary data regarding cadet illness were acquired from the historical archives of the USMA. These included annual reports, clinical admission records, casualty ledgers, and sanitation reports. Unpublished documents from the medical history of USMA provide periodic trends of health among cadets because of infectious disease.

Results

Between 1890 and 1910, the USMA at West Point was confronted with cases of influenza, measles, mumps, scarlet fever, smallpox, typhus, and malaria. In response, a series of non-pharmaceutical interventions (NPIs) were instituted to curb the spread of infectious disease. These interventions most likely proved effective in suppressing the transmission of communicable diseases. The most common and arguably the most effective NPI was the physical separation of the sick from the well.

Conclusions

The USMA experience mirrored what was occurring in the larger U.S. Army in the early 20th century and may serve as a model for the application of NPIs in response to modern infectious diseases resulting from novel or unknown etiologies.
Few Fixed Variants between Trophic Specialist Pupfish Species Reveal CandidateCis-Regulatory Alleles Underlying Rapid Craniofacial Divergence
Authors: McGirr Joseph A , Martin Christopher H
Published: September 2020

Investigating closely related species that rapidly evolved divergent feeding morphology is a powerful approach to identify genetic variation underlying variation in complex traits. This can also lead to the discovery of novel candidate genes influencing natural and clinical variation in human craniofacial phenotypes. We combined whole-genome resequencing of 258 individuals with 50 transcriptomes to identify candidate cis-acting genetic variation underlying rapidly evolving craniofacial phenotypes within an adaptive radiation of Cyprinodon pupfishes. This radiation consists of a dietary generalist species and two derived trophic niche specialists—a molluscivore and a scale-eating species. Despite extensive morphological divergence, these species only diverged 10 kya and produce fertile hybrids in the laboratory. Out of 9.3 million genome-wide SNPs and 80,012 structural variants, we found very few alleles fixed between species—only 157 SNPs and 87 deletions. Comparing gene expression across 38 purebred F1 offspring sampled at three early developmental stages, we identified 17 fixed variants within 10 kb of 12 genes that were highly differentially expressed between species. By measuring allele-specific expression in F1 hybrids from multiple crosses, we found that the majority of expression divergence between species was explained by trans-regulatory mechanisms. We also found strong evidence for two cis-regulatory alleles affecting expression divergence of two genes with putative effects on skeletal development (dync2li1 and pycr3). These results suggest that SNPs and structural variants contribute to the evolution of novel traits and highlight the utility of the San Salvador Island pupfish system as an evolutionary model for craniofacial development.
DNA targeting by subtype I-D CRISPR–Cas shows type I and type III features
Authors: Lin Jinzhong , Fuglsang Anders , Kjeldsen Anders Lynge , Sun Kaiyan , Bhoobalan-Chitty Yuvaraj , Peng Xu
Published: September 2020

Prokaryotic CRISPR–Cas immune systems are classified into six types based on their effector complexes which cleave dsDNA specifically (types I, II and V), ssRNA exclusively (type VI) or both ssRNA via a ruler mechanism and ssDNA unspecifically (type III). To date, no specific cleavage of ssDNA target has been reported for CRISPR–Cas. Here, we demonstrate dual dsDNA and ssDNA cleavage activities of a subtype I-D system which carries a type III Cas10-like large subunit, Cas10d. In addition to a specific dsDNA cleavage activity dependent on the HD domain of Cas10d, the helicase Cas3′ and a compatible protospacer adjacent motif (PAM), the subtype I-D effector complex can cleave ssDNA that is complementary in sequence to the crRNA. Significantly, the ssDNA cleavage sites occur at 6-nt intervals and the cleavage is catalysed by the backbone subunit Csc2 (Cas7), similar to the periodic cleavage of ssRNA by the backbone subunit of type III effectors. The typical type I cleavage of dsDNA combined with the exceptional 6-nt spaced cleavage of ssDNA and the presence of a type III like large subunit provide strong evidence for the subtype I-D system being an evolutionary intermediate between type I and type III CRISPR–Cas systems.
Coexistence of two quadruplex–duplex hybrids in the PIM1 gene
Authors: Tan Derrick J Y , Winnerdy Fernaldo Richtia , Lim Kah Wai , Phan Anh Tuân
Published: September 2020

The triple-negative breast cancer (TNBC), a subtype of breast cancer which lacks of targeted therapies, exhibits a poor prognosis. It was shown recently that the PIM1 oncogene is highly related to the proliferation of TNBC cells. A quadruplex–duplex hybrid (QDH) forming sequence was recently found to exist near the transcription start site of PIM1. This structure could be an attractive target for regulation of the PIM1 gene expression and thus the treatment of TNBC. Here, we present the solution structures of two QDHs that could coexist in the human PIM1 gene. Form 1 is a three-G-tetrad-layered (3+1) G-quadruplex containing a propeller loop, a lateral loop and a stem-loop made up of three G•C Watson–Crick base pairs. On the other hand, Form 2 is an anti-parallel G-quadruplex comprising two G-tetrads and a G•C•G•C tetrad; the structure has three lateral loops with the middle stem-loop made up of two Watson-Crick G•C base pairs. These structures provide valuable information for the design of G-quadruplex-specific ligands for PIM1 transcription regulation.
Curve Characteristics and Response of Sciatic and Olisthesis Scoliosis Following L5/S1 Transforaminal Lumbar Interbody Fusion in Adolescent Lumbar Spondylolisthesis
Authors: Du Chang-zhi , Zhu Ze-zhang , Wang Yu , Li Song , Xu Liang , Wang Bin , Qiu Yong , Sun Xu
Published: September 2020

BACKGROUND

Lumbosacral spondylolisthesis-induced scoliosis is a rare clinical entity. Sagittal reconstruction and the coronal curve evolution after surgery for spondylolisthesis have not been investigated in depth.

OBJECTIVE

To compare the curve characteristics between sciatic scoliosis and olisthetic scoliosis and to further investigate the effects of lumbosacral transforaminal lumbar interbody fusion (TLIF) on scoliosis evolution.

METHODS

Adolescents with sciatic scoliosis group (SS group) or olisthetic scoliosis group (OS group) who underwent L5/S1 TLIF from 2010 to 2017 and were followed up for at least 2 yr were retrospectively reviewed. Radiographic parameters and patient-reported outcomes were evaluated.

RESULTS

There were 20 patients in the SS group (M/F: 8/12; age: 15.6 ± 2.2 yr) and 16 in the OS group (M/F: 6/10; age: 16.8 ± 2.5 yr). Both groups had similar preoperative Cobb angles, but more patients with coronal imbalance were observed in the SS group. Moreover, the OS group showed significantly larger L5 tilt and rotation. After surgery, the slip reduction rate of the SS group and OS group were 76.1% ± 12.4% and 79.4% ± 9.6%, respectively. Scoliosis resolution was observed in all patients in the SS group but only in 9 patients (56.2%) in the OS group. Patients with failed scoliosis resolution in the OS group were older and had a larger Cobb angle and L5 rotation compared with those with successful scoliosis resolution.

CONCLUSION

Lumbosacral TLIF can achieve satisfactory slip reduction and scoliosis resolution. Sciatic scoliosis often presents with coronal imbalance but also a preferable curve prognosis. A large Cobb angle and L5 rotation may hinder the resolution of olisthetic scoliosis.
NEWTON-2 Cisternal (Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage): A Phase 2, Multicenter, Randomized, Open-Label Safety Study of Intracisternal EG-1962 in Aneurysmal Subarachnoid Hemorrhage
Authors: Macdonald R Loch , Hänggi Daniel , Ko Nerissa U , Darsaut Tim E , Carlson Andrew P , Wong George K , Etminan Nima , Mayer Stephan A , Aldrich E Francois , Diringer Michael N , Ng David , Strange Poul , Bleck Thomas , Grubb Robert , Suarez Jose I ,   on behalf of the NEWTON Investigators
Published: September 2020

BACKGROUND

A sustained release microparticle formulation of nimodipine (EG-1962) was developed for treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH).

OBJECTIVE

To assess safety, tolerability, and pharmacokinetics of intracisternal EG-1962 in an open-label, randomized, phase 2 study of up to 12 subjects.

METHODS

Subjects were World Federation of Neurological Surgeons grades 1 to 2, modified Fisher grades 2 to 4, and underwent aneurysm clipping within 48 h of aSAH. EG-1962, containing 600 mg nimodipine, was administered into the basal cisterns. Outcome on the extended Glasgow Outcome Scale (eGOS), pharmacokinetics, delayed cerebral ischemia and infarction, rescue therapy, and safety were evaluated.

RESULTS

The study was halted when a phase 3 study of intraventricular EG-1962 stopped because that study was unlikely to meet its primary endpoint. Six subjects were randomized (5 EG-1962 and 1 oral nimodipine). After 90-d follow-up, favorable outcome on the eGOS occurred in 1 of 5 EG-1962 and in the single oral nimodipine patient. Four EG-1962 and the oral nimodipine subject had angiographic vasospasm. One EG-1962 subject had delayed cerebral ischemia, and all subjects with angiographic vasospasm received rescue therapy except 1 EG-1962 patient. One subject treated with EG-1962 developed right internal carotid and middle cerebral artery narrowing 5 mo after placement of EG-1962, leading to occlusion and cerebral infarction. Pharmacokinetics showed similar plasma concentrations of nimodipine in both groups.

CONCLUSION

Angiographic vasospasm and unfavorable clinical outcome still occurred after placement of EG-1962. Internal carotid artery narrowing and occlusion after placement of EG-1962 in the basal cisterns has not been reported.