bluuebunny/crossref_metadata_2025 huggingface dataset:
Domestic Legislation on Cargo Liability
Authors: Girvin Stephen
Published: May 2022

This chapter discusses domestic legislation on cargo liability. In English law, common carriers, such as masters of general ships, were carriers who exercised a public employment, offering carriage to all persons wishing to use the services offered, whether for the carriage of goods (or of passengers). The general principle, as in Roman law, was that the carrier was liable as an ‘insurer’ of the goods, absolutely responsible for delivering the goods at the destination in like order and condition. Unlike public carriers, private carriers undertake the carriage of goods but do not hold themselves out as exercising a public employment. Usually, the carrier’s obligations arise from his contractual agreement to carry the goods of the shipper and, where for reward, private carriers are bailees and have the ordinary responsibilities of a bailee of the goods. The chapter then looks at the Harter Act of 1893 and legislation in other Commonwealth countries, including the Shipping and Seamen Act 1903 in New Zealand, the Sea-Carriage of Goods Act in Australia, and Canada’s Water-Carriage of Goods Act in 1910.
The Shipper’s Common Law Obligations
Authors: Girvin Stephen
Published: May 2022

This chapter explores the common law obligations of the shippers. Contracts, whether general or specific, including contracts of affreightment, contain agreed (express) terms and may, subject to interpretation, also contain implied terms. Contracts of affreightment are invariably negotiated against a background of custom and commercial usage and are commonly subject to the carriers’ standard terms and conditions of carriage and the mandatory (or contractual) application of an international convention, such as the Hague or Hague-Visby Rules. In the carriage of goods by sea, certain obligations are implied by law and will be incorporated into the contract in the absence of agreement to the contrary. Although there is no formal list of cargoes which may be dangerous, hazardous, or harmful to the carrier’s ship or other cargoes aboard the ship, various statutes recognize that the shipper has certain obligations to the carrier with regard to cargo which is ‘fraught with danger or risk; perilous, hazardous, unsafe; injurious’. The chapter then considers the obligation of shippers to nominate a safe port.
Shipper’s Obligations and Immunities under the Hague, Hague-Visby, and Rotterdam Rules
Authors: Girvin Stephen
Published: May 2022

This chapter studies the shipper’s obligations and immunities under the Hague, Hague-Visby, and Rotterdam Rules. The focus of the Hague and Hague-Visby Rules is almost exclusively the rights and immunities of the carrier. By contrast, the shipper’s position is somewhat insignificant. There is no definition and there are only two provisions of the Rules which concern the shipper’s specific duties. The first is Article III, rule 5, which provides that: ‘The shipper shall be deemed to have guaranteed to the carrier the accuracy at the time of shipment of the marks, number, quantity and weight, as furnished by him, and the shipper shall indemnify the carrier against all loss, damages and expenses arising or resulting from inaccuracies in such particulars. The right of the carrier to such indemnity shall in no way limit his responsibility and liability under the contract of carriage to any person other than the shipper’. The second is Article IV, rule 6, which contains provisions on the shipment of dangerous cargoes.
Exceptions from Liability under the Hague, Hague-Visby, and Rotterdam Rules
Authors: Girvin Stephen
Published: May 2022

This chapter evaluates the exceptions from liability under the Hague, Hague-Visby, and Rotterdam Rules. While the Hague and Hague-Visby Rules impose on the carrier the obligations in article III, rule 1, in return the carrier may rely on the provisions of article IV, such as article IV, rule 2, and various cognate provisions, such as article IV, rule 5 (limitation of liability). The catalogue of exceptions from liability may be surrendered in part but may not be added to. As a matter of interpretation, the correct approach ‘is to construe the exceptions in their own terms, while bearing in mind that they fall under a general heading and have to be construed as part of the overall scheme of obligations, liabilities and exceptions’. Meanwhile, article 17.3 of the Rotterdam Rules provides that: ‘The carrier is also relieved of all or part of its liability pursuant to paragraph 1 of this article if, alternatively to proving the absence of fault as provided in paragraph 2 of this article’, it proves that one or more of the listed events or circumstances caused or contributed to the loss, damage, or delay. The chapter then considers the protection of servants or agents of the carrier.
Limitation of Liability
Authors: Girvin Stephen
Published: May 2022

This chapter focuses on the limitation of liability under the Hague, Hague-Visby, and Rotterdam Rules. One of the distinctive features of the maritime domain is limitation of liability. As the shipowner might limit its liability to amounts that are derisory, such limits and the terms on which limitation is offered are prescribed by international conventions, including the Hague, Hague-Visby, Hamburg, and Rotterdam Rules. Additionally, limitation is available under maritime oil pollution conventions, and under two general (or tonnage) limitation conventions, the 1957 Limitation Convention, and the Convention on Limitation and Liability for Maritime Claims 1976 (LLMC 1976) and the Protocol to the latter, the LLMC 1996. In modern law, therefore, ‘the limitation of a shipowner’s liability is the creature of statutes’. The limits of liability under the carriage of goods conventions are concerned with ‘package’ limitation, which is restricted to individual and separate claims made under a contract of carriage.
Voyage Charterparties
Authors: Girvin Stephen
Published: May 2022

This chapter describes voyage charterparties. A charterparty is usually embodied in a written contract but this need not be signed. Negotiations may be concluded by correspondence even where the intended shipowner and charterer intend to embody their contract in a formal charterparty. Whether or not there is a binding contract is subject to the usual contractual rules as to formation. Whether and when the parties are ad idem and intend to be contractually bound is determined by examining the intentions of the parties and reflected in their negotiations, whether wholly or partly in writing, orally, or by conduct. Negotiations leading to a concluded agreement are today conducted by telephone, by e-mail, and instant messaging exchanges. The chapter then looks at the use of printed standard form charterparties.
Laytime and Demurrage
Authors: Girvin Stephen
Published: May 2022

This chapter explores laytime and demurrage, which is a fundamental aspect of the law relating to voyage charterparties. The period of time available for the loading and unloading of cargo is known as the laydays. The laydays are free of charge to the charterer who is usually regarded as having paid for this time in the freight. If the laydays are exceeded, the charterer has to pay compensation to the shipowner either in the form of agreed damages (demurrage) or liquidated damages (damages for detention). There are essentially two competing interests, those of the charterer and those of the shipowner. The former will wish to secure an adequate number of laydays to cover any unexpected contingencies which may arise during the process of loading or discharge of the cargo, while the latter would wish to have his ship available for sailing elsewhere in pursuance of further employment.
Damages
Authors: Girvin Stephen
Published: May 2022

This chapter reviews the law relating to damages, which is the subject of several treatises and textbooks. It looks at the basic principles before analysing some specific aspects of damages in the carriage of goods by sea. In general terms, the innocent party almost always resorts to a remedy sounding in damages, often because this is the only remedy available. It is possible to recover for losses in the tort of negligence, subject to fulfilling the usual criteria. The chapter then considers damages for not presenting bills of lading; damages under international conventions; damages for failure to load cargo; damages for failure to carry cargo; damages for delay; damages for non-delivery of cargo; deadfreight; and damages under a time charterparty.
Employment in National Law
Authors: Merrett Louise
Published: May 2022

This chapter discusses employment in national law. The starting point in England and other European countries remains a distinction between contracts of service and contracts for services, or to put it another way, between employment and self-employment. There is no single test for determining employee status in English law and the position is in many respects uncertain. The courts apply a multi-factor test, considering elements of personal subordination and also that the parties mutually agree that the employee will work and will be provided with work in the future. The courts will also consider the economic reality and the extent to which the employee can be said to be in business on his own account. However, employment rights are now increasingly given to a wider category of workers who are not employees under the strict traditional definition, but conversely are not genuinely self-employed in the sense of operating in a business-to-business context. These include casual workers, zero hours and gig economy workers, self-employed tradesmen and service providers, and agency workers. The chapter then looks at the meaning of employment in other European jurisdictions.
National Jurisdiction Rules in Employment Cases
Authors: Merrett Louise
Published: May 2022

This chapter focuses on the role of national jurisdiction rules in employment cases. Following the UK's departure from the EU, the European jurisdiction rules which previously governed international jurisdiction in European cases no longer apply. Jurisdiction in all cases is now determined by national rules. The doctrine of forum conveniens plays a crucial role in common law jurisdictions. By contrast to the rigid rules which apply under the Brussels I Regulation, the adjudicatory discretion given to courts at common law allows them to ensure that each case is heard in the most appropriate forum. In employment cases, that forum is usually where the work is carried out. It has been suggested that stays on grounds of forum conveniens should not be possible in the case of statutory employment claims in employment tribunals. However, there is clearly jurisdiction to order such a stay, and, provided there is a remedy available in another more appropriate forum, there is no reason why proceedings should not take place in that forum.
Choice of Law
Authors: Merrett Louise
Published: May 2022

This chapter assesses the choice of law rules which apply to employment contracts. At common law, if the parties had not themselves chosen a law, the applicable law was that of the country with the closest and most real connection to the contract of employment. The common law rules were replaced, first, by the Rome Convention, which itself was replaced by the Rome I Regulation and which in turn has now become part of retained EU law following the UK's exit from the EU. The choice of law rules applicable to employment contracts are now contained in specific provisions of the Rome I Regulation. Absent an express or implied choice of law, employment contracts will usually be governed by the law of the place where the employee habitually works. However, that law can be displaced if the contract is more closely connected with another jurisdiction. The question of what weight should be given to the presumption, and the proper approach to be taken to displacing it, raises difficult and fundamental issues. In particular, it raises the question of whether the underlying purpose behind the employment rules can and should be reflected in the balancing exercise. The chapter then looks at choice of law in non-contractual claims.
Looking for New Lenses
Authors: Di Noia Carmine , Filippa Luca
Published: May 2022

This chapter traces the evolution of financial market infrastructures (FMIs) mainly exchanges, central counterparties, and central securities depositories in the last 30 years. Technological innovation and the structural reforms that supported cross-border trade supported the global expansion of FMIs over the past decades. The FMIs landscape went through substantial changes not just in their business models but also in ownership structures. While exchanges, central counterparties, and central securities depositories, for a long time, used to be either public entities or mutual enterprises, they have since been transformed into for-profit companies, in many cases listed on stock exchanges. What used to be a monopolistic market structure has become a highly competitive, globalized market, where one provider's services easily can be substituted by alternatives in a large variety of marketplaces. In addition to providing indirect services to financial intermediaries, FMIs increasingly have come to offer and distribute services directly to wholesale and even retail investors, thereby reducing transaction costs and enhancing efficiency. All of this has a dramatic impact on regulation and supervision: the traditional micro-prudential and investor protection issues are now more and more intertwined with macro-stability and antitrust issues which may lead to some reshape in the institutional architecture, especially in the framework of Capital Markets Union in the European Union.
A Systemic Assessment of the Financial Market Infrastructures Landscape
Authors: Papathanassiou Chryssa
Published: May 2022

This chapter assesses the systemic relevance of financial market infrastructure (FMI) groups. It takes a closer look at the different organisational models of FMI groups and the resulting risks, and examines how these risks have been addressed in recent international standards and legislation within the US and the EU. International standard-setting bodies, such as the Committee on Payments and Market Infrastructures (CPMI) in cooperation with the International Organization of Securities Commissions (IOSCO), have long acknowledged the importance of FMIs as being at the 'core' of the global financial system. While a number of large and interconnected financial firms have failed in a spectacular manner during the recent financial crisis, no central counterparty (CCP) or any other systemically important FMI has failed despite the significant stress experienced. Following calls by the G-20 after the financial crisis, trade repositories (TRs) and CCPs have extended their services to the over-the-counter (OTC) derivatives market providing powerful risk mitigation. The chapter then turns to the treatment of FMI operators with a banking licence and their treatment in the European regulatory framework for credit institutions. Risk-sensitivity and proportionality of regulatory requirements are identified as key challenges for the application of bank capital and organisational requirements to providers of FMI.
Blockchain and the Future of Financial Market Infrastructures
Authors: Veil Rüdiger
Published: May 2022

This chapter analyses new regulatory challenges posed by new forms of the digitization of financial instruments, on the basis of blockchain and distributed ledger technology (DLT). While real-world examples for the problems posed by these new technologies continue to be rare, the chapter discusses the various forms for the digitization of financial instruments and transactions currently available. Against this backdrop, it illustrates the difficulties to adequately address the new phenomena within the existing regulatory frameworks. In many jurisdictions, traditional concepts of securities law do not (yet) provide for digitized instruments, while European financial markets regulation, depending on the design of individual trading platforms and transactions, already facilitates the establishment of new platforms trading in such instruments. However, the decentralized nature of blockchain-based financial instruments and trading transactions clearly comes with substantial challenges for residual regulatory strategies, which rely on the regulation of market operators as guardians for the preservation of market stability and investor protection. Similar problems are identified with regard to the providers of securities settlement systems.
Alternative Trading Venues in the EU
Authors: Busch Danny , Gulyás Han
Published: May 2022

This chapter looks at the market environment and regulatory framework applicable to trading platforms in the European Union (EU). It begins by introducing the relevant categories established in EU law. These include regulated markets (RMs), multilateral trading facilities (MTFs), systematic internalisers (SIs) and organised trading facilities for non-equity financial instruments (OTFs). While MTFs, the operation of which qualifies as the provision of an investment service under European law, share many characteristics of traditional exchanges (RMs), the new category of OTFs has only been introduced by the securities laws reforms introduced by the second Markets in Financial Instruments Directive (MiFID II) of 2014, and shares only some of the traditional features of regulated markets and MTFs. By contrast, SIs—the internalisation of trading activities with different parties by a financial intermediary—are not formally regulated as ‘trading venues’, although SIs also fulfil at least some of the economic functions of RMs, MTFs and in particular OTFs.
Securities and Derivatives Central Counterparties in the United States
Authors: Saguato Paolo
Published: May 2022

This chapter offers the US perspective on securities and derivatives central counterparties (CCPs) and focuses on the macro-prudential and financial stability role bestowed on CCPs by post-crisis policymakers. It unpacks the peculiar economic and governance dynamics of clearinghouses and their delicate incentives structure and focuses on the regulatory framework built by post-crisis policymakers. Interestingly, in the United States, the market and regulatory structure of securities and derivatives CCPs substantially differentiate, with securities CCPs organized as subsidiaries of a stand-alone member-owned firm, and derivatives CCPs being vertically integrated in investor-owned for-profit financial groups. The chapter looks into the two different market structures and ownership models of securities and derivatives clearinghouses and draws comparative analyses of the US and EU approaches to the regulation of clearing markets and CCPs. US derivatives investor-owned CCPs, as their EU peers, present unique agency costs between clearinghouses' members and shareholders, where the members are the final risk bearers of the business but without control rights, and the shareholders retain control rights, but with limited skin in the game. The chapter concludes with some policy considerations on how to strengthen CCPs resilience and how to more effectively mitigate the agency costs that spills from the members-shareholder divide.
Transatlantic Crossings
Authors: Haentjens Matthias
Published: May 2022

This chapter focuses on EU–US cross-border financial market infrastructures (FMIs) and the laws and regulations that govern transatlantic (i.e. cross-border) securities and derivatives transactions. It argues that the overlap of administrative law and private law in the laws and regulations of cross-border securities and derivatives increase the complexity and underlying risk of such transactions. The chapter focuses on two sets of rules that apply to securities and derivatives contracts: (1) the rules that govern the insolvency of an intermediary and investor protection; and (2) the rules for the provision of collateral. It also discusses how the complexity and diversity of conflict of laws regimes, and the diversity in substantive laws for intermediated securities, might undermine the stability of the markets. To do so, the chapter analyses the EU and US regimes for the holding of intermediated securities, the private international law provision in place to reduce jurisdictional frictions, and regulatory discontinuities between the EU and the US.
Data Reporting in the United States
Authors: Berner Richard B , Doyle Robin , Lamar Kenneth
Published: May 2022

This chapter describes the past and present regulatory reporting landscape for US swap data and financial market infrastructures (FMIs). It argues that standards are essential to ensure that both the data and the technology supporting the reporting process are fit for purpose and are dynamic enough that changing data needs are available quickly in times of stress. Moreover, US regulators must accelerate their work to harmonize US reporting requirements at home and work with those abroad to align them globally. The chapter builds on the lessons learned from current swap and FMI data reporting regimes to inform the rethinking of financial reporting generally and the process of financial regulation to make them more effective and efficient. To realize those goals, regulators and industry must learn to rely on data rather than reports and must collaborate to align their use of these data and standardize them to make them interoperable.
Ethnic and socioeconomic disparities in survival of children and adolescents with CNS tumors in Southern Israel
Authors: Abu-Quider Abed , Asleh Mahdi
Published: May 2022

Background

This study sought to evaluate survival of pediatric and adolescent patients with central nervous system (CNS) cancer in southern Israel, outline disparities between ethnic and socioeconomic groups (Bedouin Arabs compared to Jews) and evaluate the role of socioeconomic status (SES) in ethnic disparities.

Methods

A retrospective study was conducted among 91 patients aged one to 20 years, who were diagnosed with CNS tumors between 2001 and 2017, and followed-up through 2020. Ethnic differences in survival were measured by age, sex, stage, histology and SES. One and 3-year survival rates were calculated. Multivariable regression analysis was used to estimate adjusted ethnic differences in survival rates.

Results

Ethnic differences in survival existed within all studied variables. All Bedouin patients lived in low SES settlements (All Bedouin settlement in Southern Israel are ranked in lower socioeconomic deciles). Twenty-eight patients had medulloblastoma. Seven (25%) presented with leptomeningeal disease or distant metastases. Medulloblastoma molecular subgroups were not assessed for logistic reasons. Three-year overall survival of Bedouins was 50% compared to 92.3% for Jews. Adjusted risk of death at 3 years was significantly higher for Bedouin patients (aHR 3.36, 95% CI 1.41–7.98, P = .006).

Conclusions

We conclude that Bedouin children with CNS tumors have significantly lower survival rates compared to Jewish children, and SES seems to play a major part in these disparities. Factors influencing these disparities should be addressed and public health interventions to eliminate these disparities should be developed.
The Impact of Current Tobacco Product Use Definitions on Estimates of Transitions Between Cigarette and ENDS Use
Authors: Brouwer Andrew F , Levy David T , Jeon Jihyoun , Jimenez-Mendoza Evelyn , Sanchez-Romero Luz María , Mistry Ritesh , Meza Rafael
Published: May 2022

Introduction

Definitions of current tobacco and nicotine delivery product use vary and depend on frequency of use, established-use criteria, and the product type. Previous research has not considered how transition rates between current use of different products depend on the current use definition.

Aims and Methods

We applied a multistate transition model to data on U.S. adults from waves 1–4 (2013–2017) of the Population Assessment of Tobacco and Health (PATH) study. We estimated transition rates between never, non-current, cigarette, electronic nicotine delivery systems (ENDS), and dual use states with and without established-use criteria (has smoked 100+ cigarettes in their lifetime; ever fairly regularly used ENDS) and different frequency thresholds (1+, 10+, 20+, and 30 days of the past 30 days). We considered use below a frequency threshold as either non-current use or a distinct, infrequent use category.

Results

When treating use below a frequency threshold as non-current use, transition probability estimates were largely robust to the choice of use frequency threshold, although sole ENDS users were more likely to transition to non-current use or dual use as the current use threshold increased. Removing the established-use criterion for ENDS reduced the estimates of sole ENDS and dual users staying in their use state. When treating infrequent use as a separate category, transition probability estimates were dependent on the use frequency threshold, particularly transitions among the dual use states.

Conclusions

Product use definitions have important implications for assessing product use transitions and thus the public health implications of cigarette and ENDS control strategies.

Implications

How we define “current use” of tobacco and nicotine delivery products changes our estimates of how individuals transition to, between, and from different patterns of use. We show that the robustness of transition estimates to whether or not non-established users are included as current users and to different frequency-of-use threshold depends in part on whether low-frequency users are categorized as non-current users or as a distinct category. Our results emphasize the importance of intentional definitions of product use that reflect the larger goals of public health and tobacco control.
Seed Dormancy and Longevity: A Mutual Dependence or a Trade-Off?
Authors: Rehmani Muhammad Saad , Aziz Usman , Xian BaoShan , Shu Kai
Published: May 2022

Seed dormancy is an important agronomic trait in cereals and leguminous crops as low levels of seed dormancy during harvest season, coupled with high humidity, can cause preharvest sprouting. Seed longevity is another critical trait for commercial crop propagation and production, directly influencing seed germination and early seedling establishment. Both traits are precisely regulated by the integration of genetic and environmental cues. Despite the significance of these two traits in crop production, the relationship between them at the molecular level is still elusive, even with contradictory conclusions being reported. Some studies have proposed a positive correlation between seed dormancy and longevity in association with differences in seed coat permeability or seed reserve accumulation, whereas an increasing number of studies have highlighted a negative relationship, largely with respect to phytohormone-dependent pathways. In this review paper, we try to provide some insights into the interactions between regulatory mechanisms of genetic and environmental cues, which result in positive or negative relationships between seed dormancy and longevity. Finally, we conclude that further dissection of the molecular mechanism responsible for this apparently contradictory relationship between them is needed.
Matching into Plastic Surgery: Insights into the Data
Authors: Sarac Benjamin A. , Janis Jeffrey E.
Published: May 2022

Matching into plastic and reconstructive surgery residency, whether integrated or independent, is a competitive process. This article serves to examine, review, and summarize data published on both residency application processes. Through the results summarized, applicants should carefully review the objective and subjective factors used in evaluation to strategize how to make themselves as competitive as possible. Specifically, though, early review of the data presented may allow applicants time to focus on what modifiable factors still remain before their respective application seasons.
Single Center Oncoplastic Experience and Patient Satisfaction Reported via Patient Reported Outcomes
Authors: Wang Xuanji , Mathews Alexandra , Erickson Anne , Veselack Teresa , Bucholz Eleanor , Vandevender Darl , Godellas Constantine , Vaince Faaiza
Published: May 2022

Background:

Oncoplastic breast surgery (OPS) is gaining in popularity compared with traditional breast conserving surgery due to wider resections and better satisfaction with cosmetic outcomes. This study analyzed OPS versus traditional breast conserving surgery outcomes: wound complications, reoperations for margins or fat necrosis, and ipsilateral recurrence.

Methods:

This retrospective review compared 191 OPS and traditional breast conserving surgery patients on patient-related factors, primary outcomes, and patient reported outcome measures results. A propensity score method analysis using 1:1 to nearest neighbor was also performed.

Results:

OPS patients were younger, less likely to be smokers, more likely to be ER+ and PR+, and had larger specimen volumes than did traditional breast conserving surgery patients (P < 0.05). There were also differences in distribution of invasive ductal carcinoma and noninvasive disease (P < 0.05). After the propensity score method, the differences observed between the cohorts disappeared. No differences were observed between groups for wound complication, reoperation for positive margins or fat necrosis, or ipsilateral recurrence. Results of patient reported outcome measures showed greater satisfaction with breast surgery in OPS patients (P < 0.01).

Conclusions:

We showed that OPS is a noninferior technique that should be discussed with appropriate patients. Operative planning should involve patient preferences in optimizing long-term cosmetic outcomes.
A Retrospective Study of Puncture and Drainage for Primary Brainstem Hemorrhage With the Assistance of a Surgical Robot
Authors: Zhang Shuai , Chen Tao , Han Bing , Zhu Weisheng
Published: May 2022

Background:

Whether primary brainstem hemorrhage (PBH) should be treated with a conservative treatment or with surgical intervention (such as craniotomy, puncture, and drainage) is still controversial. The aim of this study was to assess the feasibility and safety of puncture and drainage for PBH with the assistance of a surgical robot.

Patients and Methods:

A total of 53 patients diagnosed with PBH were included in this study. They were divided into surgical and nonsurgical groups. All patients in the surgical group underwent puncture and drainage of PBH assisted with surgical robots at Beijing Jingmei General Hospital from June 2017 to January 2021. We evaluated this technology with radiographic and clinical results.

Results:

Postoperative computed tomography showed that all the drainage catheters had been pushed to the target point, which had been designated before the operation. After the operation, the hematoma was reduced by an average of 3.7 mL. None of the patients experienced serious surgery-related complications. Clinical follow-up revealed that 2 patients could not be followed-up, 8 died, and the rest were in disability or in a vegetative state.

Conclusions:

It may be safe, feasible, and effective to complete the puncture and drainage of PBH with the assistance of a surgical robot. This technique has fewer complications than the traditional puncture method and has high accuracy. It may be more suitable for patients with a hematoma volume of 5 to 10 mL in PBH. The amount of hematoma volume >10 mL may be associated with poor postoperative prognosis. However, high-quality cohorts or case-control studies are needed to verify the effect in this study.
Concerns About Compounded Bioidentical Menopausal Hormone Therapy
Authors: Pinkerton JoAnn V.
Published: May 2022

Following the release of the Women's Health Initiative data, women began to use compounded bioidentical hormone therapy (cBHT) in the misguided belief of greater safety and efficacy than traditional hormone therapy. New guidelines recommend government-approved hormone therapy for symptomatic healthy menopausal women younger than 60 years or within 10 years of menopause at the time of initiation. For women requesting bioidentical hormones, those similar to the hormones present before menopause, there are many government-approved hormone therapies with extensive pharmacokinetic, safety, and efficacy data provided with package inserts delineating efficacy, safety, and potential risks. For women requesting non–Food and Drug Administration–approved (cBHT), these cBHTs lack data on pharmacokinetics, safety, and efficacy and are not provided a label detailing risk. Their use should be restricted to women with allergies or dosing or formulations not available in government-approved therapies. Pellet therapy providing women with supraphysiologic hormone dosing raises even more safety concerns.
Menopausal Hormone Therapy and Breast Cancer
Authors: Chlebowski Rowan T. , Manson JoAnn E.
Published: May 2022

Associations of estrogen-alone and estrogen plus progestin with breast cancer incidence and related mortality are reviewed from observational studies (The Collaborative Group on Hormonal Factors in Breast Cancer and The Million Women Study, 2019) and the Women’s Health Initiative’s (2020) two randomized trials evaluating conjugated equine estrogen alone, for women with prior hysterectomy or with medroxyprogesterone acetate. Findings are generally concordant for estrogen plus progestin use with both observational and randomized studies reporting higher breast cancer incidence. Findings are discordant for estrogen-alone use where, in the WHI randomized trial, a lower incidence and lower breast cancer mortality was seen. In contrast, in the observational studies, estrogen-alone use was associated with higher breast cancer incidence and higher breast cancer mortality. Although these discordant findings are difficult to fully reconcile, we conclude with a discussion of public health implications of the available evidence on menopausal hormone therapy and breast cancer.
Magnetic resonance spectroscopy shows associations between neurometabolite levels and perivascular space volume in Parkinson’s disease: a pilot and feasibility study
Authors: Donahue Erin K. , Bui Vy , Foreman Ryan P. , Duran Jared J. , Venkadesh Siva , Choupan Jeiran , Van Horn John D. , Alger Jeffry R. , Jakowec Michael W. , Petzinger Giselle M. , O’Neill Joseph
Published: May 2022

Objective

Higher volume fraction of perivascular space (PVS) has recently been reported in Parkinson’s disease (PD) and related disorders. Both elevated PVS and altered levels of neurometabolites, assayed by proton magnetic resonance spectroscopy (MRS), are suspected indicators of neuroinflammation, but no published reports have concurrently examined PVS and MRS neurometabolites.

Methods

In an exploratory pilot study, we acquired multivoxel 3-T MRS using a semi-Localization by Adiabatic SElective Refocusing (sLASER) pulse-sequence (repetition time/echo time = 2810/60 ms, voxels 10 × 10 × 10 mm3) from a 2D slab sampling bilateral frontal white matter (FWM) and anterior middle cingulate cortex (aMCC). PVS maps obtained from high-resolution (0.8 × 0.8 × 0.8 mm3) T1-weighted MRI were co-registered with MRS. In each MRS voxel, PVS volume and neurometabolite levels were measured.

Results

Linear regression accounting for age, sex, and BMI found greater PVS volume for higher levels of choline-containing compounds (Cho; P = 0.047) in FWM and lower PVS volume for higher levels of N-acetyl compounds (NAA; P = 0.012) in aMCC. Since (putatively) higher Cho is associated with inflammation while NAA has anti-inflammatory properties, these observations add to evidence that higher PVS load is a sign of inflammation. Additionally, lower Montreal Cognitive Assessment scores were associated with lower NAA in aMCC (P = 0.002), suggesting that local neuronal dysfunction and inflammation contribute to cognitive impairment in PD.

Conclusion

These exploratory findings indicate that co-analysis of PVS and MRS is feasible and may help elucidate the cellular and metabolic substrates of glymphatic and inflammatory processes in PD.
Acupuncture improves the structure of spastic muscle and decreases spasticity by enhancing GABA, KCC2, and GABAAγ2 in the brainstem in rats after ischemic stroke
Authors: Sun Tian-Yi , Ma Liang-Xiao , Mu Jie-Dan , Zhang Zhou , Yu Wen-Yan , Qian Xu , Tian Yuan , Zhang Yi-Dan , Wang Jun-Xiang
Published: May 2022

Background

Increasing data show that structural changes of spastic muscle and hyperexcitability of reticulospinal tract (RST) are involved in the pathogenesis of spasticity after stroke (SAS). Our previous study has indicated that the anti-spastic effect of acupuncture, especially waggle needling (WN, a multiple directional needling method with joint movement), on SAS rats was related to the KCC2-GABAA pathway in cerebral cortex. Furthermore, as a peripheral stimulation to treat upper motor neuron injury-related spasticity, acupuncture’s effect on peripheral spastic muscles and inhibitory neurotransmitters in the brainstem, the origin of the RST, should be further clarified. This study aimed to examine the effect of acupuncture on the structure of spastic muscle and on the KCC2-GABAA pathway in the brainstem of SAS rats.

Methods

Middle cerebral artery occlusion (MCAO) or a sham operation were conducted in SD rats to establish SAS and control models. Behavioral assays, muscle myosin ATPase staining, and molecular biology technologies were used to compare different groups.

Results

In SAS models, hindlimb motor ability was decreased, neurologic deficits and spasticity were induced, the proportion of type I muscle fibers in spastic muscle was increased, and the expressions of γ-aminobutyric acid (GABA), KCC2, and the GABAAγ2 subunit of the pentameric GABAA receptor in the brainstem were decreased. Acupuncture including WN and perpendicular needling (PN) reversed these effects of MCAO. Furthermore, the therapeutic effect of WN was better than that of PN.

Conclusions

Acupuncture after MCAO improves the structure of spastic muscle and decreases spasticity probably at least partly by enhancing GABA, KCC2, and GABAAγ2 in the brainstem in SAS rats.
Saliva as an alternative specimen to nasopharyngeal swabs for COVID-19 diagnosis: Review
Authors: McPhillips Leah , MacSharry John
Published: May 2022

Almost 2 years ago, the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was discovered to be the causative agent of the disease COVID-19. Subsequently, SARS-CoV-2 has spread across the world infecting millions of people, resulting in the ongoing COVID-19 pandemic. The current ‘gold standard’ for COVID-19 diagnosis involves obtaining a nasopharyngeal swab (NPS) from the patient and testing for the presence of SARS-CoV-2 RNA in the specimen using real-time reverse transcription PCR (RT-qPCR). However, obtaining a NPS specimen is an uncomfortable and invasive procedure for the patient and is limited in its applicability to mass testing. Interest in saliva as an alternative diagnostic specimen is of increasing global research interest due to its malleability to mass testing, greater patient acceptability and overall ease of specimen collection. However, the current literature surrounding the sensitivity of saliva compared to NPS is conflicting. The aim of this review was to analyse the recent literature to assess the viability of saliva in COVID-19 diagnosis. We hypothesize that the discrepancies in the current literature are likely due to the variations in the saliva collection and processing protocols used between studies. The universal adaptation of an optimised protocol could alleviate these discrepancies and see saliva specimens be as sensitive, if not more, than NPS for COVID-19 diagnosis. Whilst saliva specimens are more complimentary to mass-testing, with the possibility of samples being collected from home, the RT-qPCR diagnostic process remains to be the rate-limiting step and therefore interest in salivary rapid antigen tests, which negate the wait-times of RT-qPCR with results available within 15–30 min, may be an answer to this.
Characterization of a dynamic self-replicating mammalian expression vector based on the circular ssDNA genome of beak and feather disease virus
Authors: de Moor Warren R. J. , Regnard Guy L. , Rybicki Edward P. , Williamson Anna-Lise
Published: May 2022

In vivo nucleic expression technologies using DNA or mRNA offer several advantages for recombinant gene expression. Their inherent ability to generate natively expressed recombinant proteins and antigens allows these technologies to mimic foreign gene expression without infection. Furthermore, foreign nucleic acid fragments have an inherent ability to act as natural immune adjuvants and stimulate innate pathogen- and DNA damage-associated receptors that are responsible for activating pathogen-associated molecular pattern (PAMP) and DNA damage-associated molecular pattern (DAMP) signalling pathways. This makes nucleic-acid-based expression technologies attractive for a wide range of vaccine and oncolytic immunotherapeutic uses. Recently, RNA vaccines have demonstrated their efficacy in generating strong humoral and cellular immune responses for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). DNA vaccines, which are more stable and easier to manufacture, generate similar immune responses to RNA, but typically exhibit lower immunogenicity. Here we report on a novel method of constructing self-amplifying DNA expression vectors that have the potential to amplify and enhance gene/antigen expression at a cellular level by increasing per cell gene copy numbers, boost genomic adjuvating effects and mitigate through replication many of the problems faced by non-replicating vectors such as degradation, methylation and gene silencing. These vectors employ a viral origin rolling circle replication cycle in mammalian host cells that amplifies the vector and gene of interest (GOI) copy number, maintaining themselves as nuclear episomes. We show that these vectors maintain persistently elevated GOI expression levels at the cellular level and induce morphological cellular alterations synonymous with increased cellular stress.
In silico modelling demonstrates that user variability during tumor measurement can affect in vivo therapeutic efficacy outcomes
Authors: Murkin Jake T. , Amos Hope E. , Brough Daniel W. , Turley Karl D.
Published: May 2022

User measurement bias during subcutaneous tumor measurement is a source of variation in preclinical in vivo studies. We investigated whether this user variability could impact efficacy study outcomes, in the form of the false negative result rate when comparing treated and control groups.

Two tumor measurement methods were compared; calipers which rely on manual measurement, and an automatic 3D and thermal imaging device. Tumor growth curve data were used to create an in silico efficacy study with control and treated groups. Before applying user variability, treatment group tumor volumes were statistically different to the control group. Utilizing data collected from 15 different users across 9 in vivo studies, user measurement variability was computed for both methods and simulation was used to investigate its impact on the in silico study outcome.

User variability produced a false negative result in 3.5% to 19.5% of simulated studies when using calipers, depending on treatment efficacy. When using an imaging device with lower user variability this was reduced to 0.0% to 2.4%, demonstrating that user variability impacts study outcomes and the ability to detect treatment effect.

Reducing variability in efficacy studies can increase confidence in efficacy study outcomes without altering group sizes. By using a measurement device with lower user variability, the chance of missing a therapeutic effect can be reduced and time and resources spent pursuing false results could be saved. This improvement in data quality is of particular interest in discovery and dosing studies, where being able to detect small differences between groups is crucial.
Lola-I is a developmentally regulated promoter pioneer factor
Authors: Ramalingam Vivekanandan , Yu Xinyang , Slaughter Brian D. , Unruh Jay R. , Brennan Kaelan J. , Onyshchenko Anastasiia , Lange Jeffrey J. , Natarajan Malini , Buck Michael , Zeitlinger Julia
Published: May 2022

While enhancers are often regulated at the level of accessibility by pioneer factors, promoters tend to be constitutively accessible and poised for activation by paused Pol II — thus are often not considered as sites of developmental regulation. Here we show that the accessibility of promoters and the acquisition of paused Pol II can be subject to developmental regulation by pioneer factors. We show that Lola-I, aDrosophilazinc finger transcription factor, is ubiquitously expressed at the end of embryogenesis and causes its target promoters to become accessible and acquire paused Pol II throughout the embryo. This promoter transition is required but not sufficient for tissue-specific target gene expression. Lola-I mediates this function by binding to the edges of the promoter nucleosomes, which leads to their depletion, similar to the action of pioneer factors at enhancers. These results uncover a level of regulation for promoters that is normally found at enhancers, providing further evidence that promoters and enhancers display unexpectedly similar characteristics.
Optimizing Oscillators for Specific Tasks Predicts Preferred Biochemical Implementations
Authors: Agrahar Chaitra , Rust Michael J
Published: May 2022

Oscillatory processes are used throughout cell biology to control time-varying physiology including the cell cycle, circadian rhythms, and developmental patterning. It has long been understood that free-running oscillations require feedback loops where the activity of one component depends on the concentration of another. Oscillator motifs have been classified by the positive or negative net logic of these loops. However, each feedback loop can be implemented by regulation of either the production step or the removal step. These possibilities are not equivalent because of the underlying structure of biochemical kinetics. By computationally searching over these possibilities, we find that certain molecular implementations are much more likely to produce stable oscillations. These preferred molecular implementations are found in many natural systems, but not typically in artificial oscillators, suggesting a design principle for future synthetic biology. Finally, we develop an approach to oscillator function across different reaction networks by evaluating the biosynthetic cost needed to achieve a given phase coherence. This analysis predicts that phase drift is most efficiently suppressed by delayed negative feedback loop architectures that operate without positive feedback.

PACS numbers

47.15.-x